VPS35

Summary

VPS35 (VPS35 retromer complex component, HGNC:13487) is a protein-coding gene on chromosome 16q11.2, encoding Vacuolar protein sorting-associated protein 35 (Q96QK1). Acts as a component of the retromer cargo-selective complex (CSC). It is a selective cancer dependency (DepMap: 66.8% of cell lines).

This gene belongs to a group of vacuolar protein sorting (VPS) genes. The encoded protein is a component of a large multimeric complex, termed the retromer complex, involved in retrograde transport of proteins from endosomes to the trans-Golgi network. The close structural similarity between the yeast and human proteins that make up this complex suggests a similarity in function. Expression studies in yeast and mammalian cells indicate that this protein interacts directly with VPS35, which serves as the core of the retromer complex.

Source: NCBI Gene 55737 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Parkinson disease (Definitive, ClinGen) — +3 more curated relationships
• Clinical variants (ClinVar): 288 total — 1 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 37
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 66.8% of screened cell lines
• MANE Select transcript: NM_018206

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13487
Approved symbol	VPS35
Name	VPS35 retromer complex component
Location	16q11.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10752, MEM3, PARK17
Ensembl gene	ENSG00000069329
Ensembl biotype	protein_coding
OMIM	601501
Entrez	55737

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 15 protein_coding, 6 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000299138, ENST00000562420, ENST00000563884, ENST00000563984, ENST00000565228, ENST00000568191, ENST00000568612, ENST00000568642, ENST00000568784, ENST00000569950, ENST00000647959, ENST00000904858, ENST00000904859, ENST00000904860, ENST00000904861, ENST00000904862, ENST00000904863, ENST00000904864, ENST00000904865, ENST00000921303, ENST00000921304, ENST00000921305, ENST00000940929, ENST00000940930, ENST00000940931

RefSeq mRNA: 1 — MANE Select: NM_018206 NM_018206

CCDS: CCDS10721

Canonical transcript exons

ENST00000299138 — 17 exons

Exon	Start	End
ENSE00001324467	46656132	46660651
ENSE00001370884	46689131	46689178
ENSE00003462295	46680671	46680853
ENSE00003466377	46682079	46682175
ENSE00003482608	46678943	46679156
ENSE00003500189	46674314	46674462
ENSE00003520515	46672265	46672472
ENSE00003528700	46662983	46663162
ENSE00003545714	46668930	46669052
ENSE00003552095	46662243	46662482
ENSE00003590505	46671705	46671860
ENSE00003614117	46677315	46677398
ENSE00003619992	46676583	46676692
ENSE00003632461	46674564	46674660
ENSE00003647410	46683508	46683606
ENSE00003651100	46681377	46681500
ENSE00003689527	46661718	46661861

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 97.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 37.1671 / max 686.9537, expressed in 1817 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157198	37.1064	1817
157197	0.0607	15

Top tissues by expression

151 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	97.51	gold quality
adrenal tissue	UBERON:0018303	96.77	gold quality
corpus callosum	UBERON:0002336	96.65	gold quality
embryo	UBERON:0000922	96.56	gold quality
ganglionic eminence	UBERON:0004023	96.56	gold quality
superior frontal gyrus	UBERON:0002661	96.20	gold quality
cortical plate	UBERON:0005343	96.20	gold quality
duodenum	UBERON:0002114	96.11	gold quality
calcaneal tendon	UBERON:0003701	96.05	gold quality
islet of Langerhans	UBERON:0000006	95.88	gold quality
endometrium	UBERON:0001295	95.83	gold quality
monocyte	CL:0000576	95.70	gold quality
colonic epithelium	UBERON:0000397	95.61	gold quality
leukocyte	CL:0000738	95.51	gold quality
tonsil	UBERON:0002372	95.31	gold quality
prefrontal cortex	UBERON:0000451	95.20	gold quality
smooth muscle tissue	UBERON:0001135	95.04	gold quality
rectum	UBERON:0001052	94.83	gold quality
placenta	UBERON:0001987	94.55	gold quality
urinary bladder	UBERON:0001255	94.50	gold quality
vermiform appendix	UBERON:0001154	94.45	gold quality
blood	UBERON:0000178	94.29	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.29	gold quality
bone marrow cell	CL:0002092	94.15	gold quality
gall bladder	UBERON:0002110	93.89	gold quality
stromal cell of endometrium	CL:0002255	93.76	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.76	gold quality
frontal cortex	UBERON:0001870	93.50	gold quality
frontal lobe	UBERON:0016525	93.50	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.43	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
DNM1L	Activation
LAMP1	Repression
LAMP2	Activation
SNCA	Repression
VPS26A	Activation

miRNA regulators (miRDB)

175 targeting VPS35, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-145-5P	99.92	71.13	1836

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 66.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• These observations indicate that the mammalian retromer complex assembles by sequential association of SNX1/2 and Vps26-Vps29-Vps35 subcomplexes on endosomal membranes and that SNX1 and SNX2 play interchangeable but essential roles. (PMID:17101778)
• crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 acts as a scaffold for the carboxy-terminal half of VPS35 (PMID:17891154)
• Membrane recruitment of the cargo-selective retromer subcomplex VPS35/29/26 is catalysed by the small GTPase Rab7 and inhibited by the Rab-GAP TBC1D5. (PMID:19531583)
• Depletion of the retromer by siRNA against Vps35 leads to mis-sorting of DMT1-II to LAMP2-positive structures, and expression of siRNA-resistant Vps35 can rescue this effect. (PMID:20164305)
• Vps35 mediates vesicle transport between the mitochondria and peroxisomes. (PMID:20619655)
• Knockdown of retromer protein VPS35 activity produces no change in the quantity or cellular distribution of total cellular amyloid precursor protein (APP) and has no affect on internalization of cell-surface APP. (PMID:21515373)
• Frameshift mutations of VPS genes and losses of expression of Vps13A and Vps35 proteins are common in gastric cancers and colorectal cancers with high microsatellite instability. (PMID:21733561)
• Disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process led to Parkinson disease. (PMID:21763482)
• Only a single heterozygous variant in the VPS35 gene caused late-onset Parkinson disease in this family. (PMID:21763483)
• The amino-terminal conserved, glutamate-rich sequence of herpesvirus saimiri Tip specifically interacts with the human retromer subunit Vps35 and inhibits retromer activity. (PMID:21849449)
• The results of this study concluded that VPS35 c.1858G>A mutation is an uncommon cause of familial Parkinson’s disease. (PMID:22154191)
• Failed to find any case of VPS35 pAsp620Asn mutation in a cohort of Italian patients with familial Parkinson disease. (PMID:22278960)
• Hence, our data do not support a major role for VPS35 variations in the genetic etiology of Lewy body disorders in the Flanders-Belgian population. (PMID:22336192)
• This study suggested that VPS35 Asp620Asn may be not associated with PD in Chinese population. (PMID:22410496)
• Data show that a component of the WASH regulatory complex (SHRC), FAM21, directly interacts with the retromer CSC protein VPS35. (PMID:22513087)
• We have extended the number of autosomal dominant PD families with VPS35 mutations to 13 families, worldwide; D620N is the most frequent. (PMID:22517097)
• VPS35 variants are not associated with Parkinson’s disease in the mainland Chinese population. (PMID:22673036)
• VPS35 mutations are a rare cause of PD in different populations. (PMID:22801713)
• result suggests that mutation in the VPS35 coding region probably does not represent a major cause of late-onset Parkinson Disease in the Chinese Han population. (PMID:22891780)
• This study reported that VPS35 mutation in Japanese patients with typical Parkinson’s disease. (PMID:22991136)
• Our study apart from identifying the p.Asp620Asn variant in familial cases also identified it in idiopathic Parkinson disease cases, and thus provides genetic evidence for a role of p.Asp620Asn in Parkinson disease in different populations worldwide. (PMID:23125461)
• Mutations in VPS35 were found to not play a role in Parkinson disease patients from Southwest China. (PMID:23261770)
• There is no evidence for an overall contribution of genetic variability in VPS35 (or EIF4G1) to Parkinson disease development in this large family. (PMID:23408866)
• Pathogenic mutation in VPS35 impairs its protection against MPP(+) cytotoxicity in dopaminergic neurons in Parkinson’s disease. (PMID:23411763)
• Pathogenic VPS35 mutations provide important insights into novel molecular targets for parkinson disease. (PMID:23536430)
• Its mutation causes Parkinson’s disease in Indian population. (PMID:23726718)
• Dominant expression of Vps35 D620N mutation results in endosomal trafficking alterations that may underpin its role in PD. (PMID:24152121)
• In 2011 two groups reported the identification of the same missense mutation (p.Asp620Asn) in the vacuolar protein sorting 35 (VPS35) gene, as a novel cause of autosomal dominant parkinson disease. (PMID:24262182)
• dominant VPS35 mutations lead to neurodegeneration in Parkinson’s disease. (PMID:24740878)
• D620N mutation in VPS35 restricts WASH complex recruitment to endosomes, inhibiting autophagy. The autophagy defects can be explained, at least in part, by abnormal trafficking of the autophagy protein ATG9A. (PMID:24819384)
• Its mutation is not a common cause of familial Parkinson’s disease. (PMID:24854799)
• the major defect of the D620N mutation in the retromer component VPS35 lies in the association to the actin-nucleating Wiskott-Aldrich syndrome and SCAR homolog (WASH) complex. (PMID:24980502)
• provides molecular insights into the essential role of Vps26 and Vps35 in Rab7-mediated recruitment of the core retromer complex (PMID:25367362)
• Mutagenesis studies coupled with coimmunoprecipitations revealed that retromer-mediated trafficking requires the Env cytoplasmic tail that we show binds directly to retromer components Vps35 and Vps26. (PMID:25393110)
• VPS35 p.D620N is loss-of-function mutation with respect to VPS35 regulating synaptic transmission and AMPA-type glutamate receptors recycling in mouse cortical neurons and dopamine neuron-like cells produced from stem cells of human p.D620N carriers. (PMID:25416282)
• This study demonstrated that Genetic variability of VPS35 in parkinsonism. (PMID:25475142)
• Data indicate that vesicular transport proteins VPS35 and VPS29 influence the levels of the other subunit of retromer. (PMID:25937119)
• findings provide evidence that the VPS35 D620N mutation likely confers pathogenicity through a partial loss of function mechanism and that this may be linked to other known pathogenic mechanisms such as mitochondrial dysfunction (PMID:26251041)
• VPS35 D620N and EIF4G1 R1205H mutations are not a common cause of Parkinson disease in the Greek population. (PMID:26300542)
• neither the R120W nor the N370S variant of the GBA gene nor D620N mutation of the VPS35 gene were detected among the Parkinson disease cases or the controls. (PMID:26547032)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	vps35	ENSDARG00000008224
mus_musculus	Vps35	ENSMUSG00000031696
rattus_norvegicus	Vps35	ENSRNOG00000017612
drosophila_melanogaster	Vps35	FBGN0034708
caenorhabditis_elegans		WBGENE00006933

Protein

Protein identifiers

Vacuolar protein sorting-associated protein 35 — Q96QK1 (reviewed: Q96QK1)

Alternative names: Maternal-embryonic 3, Vesicle protein sorting 35

All UniProt accessions (4): Q96QK1, A0A3B3ITD4, H3BRJ7, I3L4S0

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a component of the retromer cargo-selective complex (CSC). The CSC is believed to be the core functional component of retromer or respective retromer complex variants acting to prevent missorting of selected transmembrane cargo proteins into the lysosomal degradation pathway. The recruitment of the CSC to the endosomal membrane involves RAB7A and SNX3. The CSC seems to associate with the cytoplasmic domain of cargo proteins predominantly via VPS35; however, these interactions seem to be of low affinity and retromer SNX proteins may also contribute to cargo selectivity thus questioning the classical function of the CSC. The SNX-BAR retromer mediates retrograde transport of cargo proteins from endosomes to the trans-Golgi network (TGN) and is involved in endosome-to-plasma membrane transport for cargo protein recycling. The SNX3-retromer mediates the retrograde endosome-to-TGN transport of WLS distinct from the SNX-BAR retromer pathway. The SNX27-retromer is believed to be involved in endosome-to-plasma membrane trafficking and recycling of a broad spectrum of cargo proteins. The CSC seems to act as recruitment hub for other proteins, such as the WASH complex and TBC1D5. Required for retrograde transport of lysosomal enzyme receptor IGF2R and SLC11A2. Required to regulate transcytosis of the polymeric immunoglobulin receptor (pIgR-pIgA). Required for endosomal localization of WASHC2C. Mediates the association of the CSC with the WASH complex via WASHC2. Required for the endosomal localization of TBC1D5. (Microbial infection) The heterotrimeric retromer cargo-selective complex (CSC) mediates the exit of human papillomavirus from the early endosome and the delivery to the Golgi apparatus.

Subunit / interactions. Component of the heterotrimeric retromer cargo-selective complex (CSC), also decribed as vacuolar protein sorting subcomplex (VPS), formed by VPS26 (VPS26A or VPS26B), VPS29 and VPS35. The CSC has a highly elongated structure with VPS26 and VPS29 binding independently at opposite distal ends of VPS35 as central platform. The CSC is believed to associate with variable sorting nexins to form functionally distinct retromer complex variants. The originally described retromer complex (also called SNX-BAR retromer) is a pentamer containing the CSC and a heterodimeric membrane-deforming subcomplex formed between SNX1 or SNX2 and SNX5 or SNX6 (also called SNX-BAR subcomplex); the respective CSC and SNX-BAR subcomplexes associate with low affinity. The CSC associates with SNX3 to form a SNX3-retromer complex. The CSC associates with SNX27, the WASH complex and the SNX-BAR subcomplex to form the SNX27-retromer complex. Interacts with VPS26A, VPS26B, VPS29, SNX1, SNX2, IGF2R, SNX3, GOLPH3, LRRK2, SLC11A2, WASHC2A, WASHC2C, FKBP15, WASHC1, RAB7A, SNX27, WASHC5, EHD1. Interacts with MAGEL2; leading to recruitment of the TRIM27:MAGEL2 E3 ubiquitin ligase complex retromer-containing endosomes. Interacts with SORCS2. (Microbial infection) Interacts with human papillomavirus 16 minor capsid protein L2 (via C-terminus); this interaction mediates the transport of the capsid from the early endosome to the Golgi apparatus.

Subcellular location. Cytoplasm. Membrane. Endosome. Early endosome. Late endosome.

Tissue specificity. Ubiquitous. Highly expressed in heart, brain, placenta, skeletal muscle, spleen, thymus, testis, ovary, small intestine, kidney and colon.

Disease relevance. Parkinson disease 17 (PARK17) [MIM:614203] An autosomal dominant, adult-onset form of Parkinson disease. Parkinson disease is a complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the VPS35 family.

RefSeq proteins (1): NP_060676* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005378	Vps35	Family
IPR016024	ARM-type_fold	Homologous_superfamily
IPR042491	Vps35_C	Homologous_superfamily

Pfam: PF03635

UniProt features (80 total): helix 44, sequence variant 11, sequence conflict 7, strand 5, region of interest 4, turn 3, modified residue 3, mutagenesis site 2, chain 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
8R0J	X-RAY DIFFRACTION	2.4
8R02	X-RAY DIFFRACTION	2.5
5OSI	X-RAY DIFFRACTION	2.52
5F0J	X-RAY DIFFRACTION	2.7
5F0P	X-RAY DIFFRACTION	2.78
2R17	X-RAY DIFFRACTION	2.8
5F0K	X-RAY DIFFRACTION	3.07
5F0M	X-RAY DIFFRACTION	3.1
8RKS	X-RAY DIFFRACTION	3.1
5F0L	X-RAY DIFFRACTION	3.2
5OSH	X-RAY DIFFRACTION	4.3
7BLN	ELECTRON MICROSCOPY	8.9
7BLO	ELECTRON MICROSCOPY	9.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96QK1-F1	91.40	0.74

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 7, 783, 791

Mutagenesis-validated functional residues (2):

Position	Phenotype
108	disrupts interaction with vps26; no effect on interaction with vps29.
675	disrupts interaction with vps29. does not effect interaction with vps26.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3238698	WNT ligand biogenesis and trafficking

MSigDB gene sets: 437 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_POSITIVE_REGULATION_OF_MITOCHONDRIAL_FISSION, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_LYSOSOMAL_TRANSPORT, GOBP_BEHAVIOR, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_VACUOLE_ORGANIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_INFLAMMATORY_RESPONSE, GOBP_SYNAPSE_ASSEMBLY, GOCC_VACUOLAR_MEMBRANE

GO Biological Process (46): intracellular protein transport (GO:0006886), lysosome organization (GO:0007040), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), regulation of mitochondrion organization (GO:0010821), Wnt signaling pathway (GO:0016055), regulation of macroautophagy (GO:0016241), regulation of protein stability (GO:0031647), protein destabilization (GO:0031648), endocytic recycling (GO:0032456), negative regulation of protein homooligomerization (GO:0032463), protein localization to endosome (GO:0036010), retrograde transport, endosome to Golgi (GO:0042147), mitochondrial fragmentation involved in apoptotic process (GO:0043653), transcytosis (GO:0045056), positive regulation of protein catabolic process (GO:0045732), negative regulation of inflammatory response (GO:0050728), modulation of chemical synaptic transmission (GO:0050804), voluntary musculoskeletal movement (GO:0050882), regulation of protein metabolic process (GO:0051246), positive regulation of dopamine receptor signaling pathway (GO:0060161), positive regulation of Wnt protein secretion (GO:0061357), regulation of synapse maturation (GO:0090128), positive regulation of mitochondrial fission (GO:0090141), positive regulation of canonical Wnt signaling pathway (GO:0090263), positive regulation of locomotion involved in locomotory behavior (GO:0090326), neurotransmitter receptor transport, endosome to postsynaptic membrane (GO:0098887), vesicle-mediated transport in synapse (GO:0099003), mitochondrion to lysosome vesicle-mediated transport (GO:0099074), neurotransmitter receptor transport, endosome to plasma membrane (GO:0099639), regulation of postsynapse assembly (GO:0150052), negative regulation of late endosome to lysosome transport (GO:1902823), regulation of dendritic spine maintenance (GO:1902950), positive regulation of dopamine biosynthetic process (GO:1903181), negative regulation of protein localization (GO:1903828), positive regulation of protein localization to cell periphery (GO:1904377), negative regulation of lysosomal protein catabolic process (GO:1905166), regulation of presynapse assembly (GO:1905606), regulation of terminal button organization (GO:2000331), positive regulation of signal transduction (GO:0009967)

GO Molecular Function (2): D1 dopamine receptor binding (GO:0031748), protein binding (GO:0005515)

GO Cellular Component (24): lysosome (GO:0005764), lysosomal membrane (GO:0005765), endosome (GO:0005768), early endosome (GO:0005769), late endosome (GO:0005770), cytosol (GO:0005829), endosome membrane (GO:0010008), postsynaptic density (GO:0014069), retromer complex (GO:0030904), retromer, cargo-selective complex (GO:0030906), neuron projection (GO:0043005), neuronal cell body (GO:0043025), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), tubular endosome (GO:0097422), dopaminergic synapse (GO:0098691), presynapse (GO:0098793), glutamatergic synapse (GO:0098978), mitochondrion-derived vesicle (GO:0099073), cytoplasm (GO:0005737), mitochondrion (GO:0005739), membrane (GO:0016020), synapse (GO:0045202), postsynapse (GO:0098794)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signaling by WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
endosome	4
synapse	3
gene expression	2
regulation of gene expression	2
endosomal transport	2
endomembrane system	2
cytoplasmic vesicle	2
cytoplasm	2
membrane protein complex	2
intracellular protein localization	1
protein transport	1
intracellular transport	1
lytic vacuole organization	1
positive regulation of macromolecule biosynthetic process	1
negative regulation of macromolecule biosynthetic process	1
mitochondrion organization	1
regulation of organelle organization	1
cell surface receptor signaling pathway	1
regulation of autophagy	1
macroautophagy	1
regulation of biological quality	1
regulation of protein stability	1
vesicle-mediated transport to the plasma membrane	1
negative regulation of protein oligomerization	1
regulation of protein homooligomerization	1
protein homooligomerization	1
protein localization to organelle	1
intercellular transport	1
cytosolic transport	1
apoptotic mitochondrial changes	1
vesicle-mediated transport	1
multicellular organismal process	1
positive regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
positive regulation of protein metabolic process	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1

Protein interactions and networks

STRING

3056 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VPS35	SNX1	Q13596	999
VPS35	VPS26A	O75436	999
VPS35	VPS26B	Q4G0F5	999
VPS35	VPS29	Q9UBQ0	999
VPS35	SNX2	P82862	997
VPS35	SNX3	O60493	994
VPS35	SNX5	Q9Y5X3	990
VPS35	SNX6	Q9UNH7	964
VPS35	SNX27	Q96L92	957
VPS35	DNAJC13	O75165	904
VPS35	PRKN	O60260	898
VPS35	EIF4G1	Q04637	898
VPS35	TBC1D5	Q92609	874
VPS35	LRRK2	Q5S007	863
VPS35	ATP13A2	Q9NQ11	853

IntAct

225 interactions, top by confidence:

A	B	Type	Score
VPS35	VPS26A	psi-mi:“MI:0915”(physical association)	0.980
VPS26A	VPS35	psi-mi:“MI:0915”(physical association)	0.980
VPS35	VPS26A	psi-mi:“MI:0914”(association)	0.980
VPS35	VPS26A	psi-mi:“MI:0407”(direct interaction)	0.980
VPS35	VPS29	psi-mi:“MI:0915”(physical association)	0.970
VPS29	VPS35	psi-mi:“MI:0915”(physical association)	0.970
VPS29	VPS35	psi-mi:“MI:0407”(direct interaction)	0.970
VPS35	VPS29	psi-mi:“MI:0407”(direct interaction)	0.970
VPS29	VPS26A	psi-mi:“MI:0914”(association)	0.930
VPS26B	VPS35	psi-mi:“MI:0915”(physical association)	0.910
VPS29	TBC1D5	psi-mi:“MI:0914”(association)	0.860
VPS26A	TBC1D5	psi-mi:“MI:0914”(association)	0.810
TBC1D5	VPS26A	psi-mi:“MI:0914”(association)	0.810
VPS29	CCDC22	psi-mi:“MI:0914”(association)	0.790
VPS29	VPS26C	psi-mi:“MI:0914”(association)	0.760

BioGRID (388): VPS35 (Two-hybrid), VPS35 (Affinity Capture-RNA), VPS35 (Affinity Capture-RNA), VPS35 (Affinity Capture-RNA), VPS35 (Affinity Capture-MS), VPS35 (Affinity Capture-MS), VPS35 (Affinity Capture-MS), VPS35 (Affinity Capture-MS), SNX3 (Reconstituted Complex), VPS35 (Reconstituted Complex), SLC11A2 (Reconstituted Complex), VPS26A (Reconstituted Complex), VPS29 (Reconstituted Complex), VPS35 (Affinity Capture-RNA), SAC3D1 (Co-fractionation)

ESM2 similar proteins: A0A0R4ITC5, A1L1F4, A4L9P7, E9Q8I9, F1MKX4, F1QFR9, F1R2X6, F8VPU6, O94915, P21359, P42345, P42346, P51593, P97526, Q04690, Q14997, Q29RF7, Q2HJG5, Q498H0, Q4KLU7, Q4QXM3, Q4VA53, Q5F3U9, Q5F3V3, Q5R6J0, Q5SSW2, Q5TBA9, Q5U241, Q5VYK3, Q6A026, Q6DDM4, Q6GP04, Q6NRP2, Q6P4S8, Q6PDI5, Q6TRW4, Q7PX35, Q7TMY8, Q7Z3U7, Q7Z6Z7

Diamond homologs: A8R7K9, F4I0P8, O74552, P34110, Q2HJG5, Q54C24, Q7X659, Q96QK1, Q9EQH3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PTCHD1	“up-regulates quantity”	VPS35	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 152 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
endocytic recycling	9	17.8×	7e-07
retrograde transport, endosome to Golgi	10	15.2×	6e-07
endosomal transport	6	10.8×	3e-03
protein transport	22	7.2×	5e-10
endocytosis	9	6.3×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

288 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	3
Uncertain significance	125
Likely benign	86
Benign	26

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
30196	NM_018206.6(VPS35):c.1858G>A (p.Asp620Asn)	Pathogenic
208774	NM_018206.6(VPS35):c.1463A>G (p.Gln488Arg)	Likely pathogenic
4278242	NM_018206.6(VPS35):c.2146C>G (p.Gln716Glu)	Likely pathogenic
930214	t(10;16)(q26;q11)	Likely pathogenic

SpliceAI

2670 predictions. Top by Δscore:

Variant	Effect	Δscore
16:46660466:T:TA	donor_gain	1.0000
16:46661711:CACT:C	donor_loss	1.0000
16:46661712:ACTT:A	donor_loss	1.0000
16:46661713:CTT:C	donor_loss	1.0000
16:46661714:TTA:T	donor_loss	1.0000
16:46661715:T:TG	donor_loss	1.0000
16:46661716:A:AC	donor_gain	1.0000
16:46661716:A:T	donor_loss	1.0000
16:46661717:C:CA	donor_loss	1.0000
16:46661717:C:CC	donor_gain	1.0000
16:46661862:C:CC	acceptor_gain	1.0000
16:46662241:ACCT:A	donor_gain	1.0000
16:46662242:CCTC:C	donor_gain	1.0000
16:46662244:T:TA	donor_gain	1.0000
16:46662480:TGCCT:T	acceptor_loss	1.0000
16:46662481:GCC:G	acceptor_loss	1.0000
16:46662482:CCTAG:C	acceptor_loss	1.0000
16:46663159:CATC:C	acceptor_gain	1.0000
16:46663161:TCC:T	acceptor_loss	1.0000
16:46663163:C:A	acceptor_loss	1.0000
16:46663164:T:C	acceptor_loss	1.0000
16:46668929:CCA:C	donor_gain	1.0000
16:46669065:CAT:C	acceptor_gain	1.0000
16:46669067:T:C	acceptor_gain	1.0000
16:46669067:T:TC	acceptor_gain	1.0000
16:46671701:ATAC:A	donor_gain	1.0000
16:46671702:T:C	donor_gain	1.0000
16:46671703:A:AC	donor_gain	1.0000
16:46671703:A:C	donor_loss	1.0000
16:46671704:C:CC	donor_gain	1.0000

AlphaMissense

5286 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:46662331:A:G	L660P	1.000
16:46662431:C:G	A627P	1.000
16:46663050:C:T	G587E	1.000
16:46663051:C:G	G587R	1.000
16:46663051:C:T	G587R	1.000
16:46663056:A:G	L585P	1.000
16:46663062:A:G	L583P	1.000
16:46668961:A:G	L539P	1.000
16:46668991:A:G	L529P	1.000
16:46669006:C:G	R524P	1.000
16:46669036:C:G	R514P	1.000
16:46672431:A:G	L401P	1.000
16:46672440:A:G	L398P	1.000
16:46674356:A:G	L373P	1.000
16:46674401:G:T	A358D	1.000
16:46674402:C:G	A358P	1.000
16:46674404:A:G	L357P	1.000
16:46674413:A:G	L354P	1.000
16:46674600:A:C	F325L	1.000
16:46674600:A:T	F325L	1.000
16:46674602:A:G	F325L	1.000
16:46674656:C:G	A307P	1.000
16:46674658:A:G	L306S	1.000
16:46674660:T:A	R305S	1.000
16:46674660:T:G	R305S	1.000
16:46676583:C:A	R305I	1.000
16:46676583:C:G	R305T	1.000
16:46676584:T:C	R305G	1.000
16:46676649:A:G	L283P	1.000
16:46676670:A:G	L276P	1.000

dbSNP variants (sampled 300 via entrez): RS1000102437 (16:46657188 T>C), RS1000114746 (16:46670190 A>C,G), RS1000341322 (16:46678072 G>A,C), RS1000541108 (16:46656880 C>T), RS1000954989 (16:46675874 A>G), RS1000978565 (16:46664463 T>C), RS1001066360 (16:46687283 T>C), RS1001144196 (16:46689865 G>A,C,T), RS1001161056 (16:46686289 G>C), RS1001171055 (16:46678722 A>G), RS1001175364 (16:46690137 A>G), RS1001531520 (16:46663942 C>T), RS1001613992 (16:46661026 A>G), RS1001641725 (16:46660771 A>G), RS1001671530 (16:46670445 A>G)

Disease associations

OMIM: gene MIM:601501 | disease phenotypes: MIM:614203, MIM:168600

GenCC curated gene-disease

Disease	Classification	Inheritance
Parkinson disease	Definitive	Autosomal dominant
Parkinson disease 17	Strong	Autosomal dominant
hereditary late onset Parkinson disease	Supportive	Autosomal dominant
intellectual disability	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Parkinson disease	Definitive	AD

Mondo (6): Parkinson disease 17 (MONDO:0013625), Parkinson disease (MONDO:0005180), glioma (MONDO:0021042), late-onset Parkinson disease (MONDO:0008199), intellectual disability (MONDO:0001071), (MONDO:0018466)

Orphanet (3): Hereditary late-onset Parkinson disease (Orphanet:411602), Glial tumor (Orphanet:182067), NON RARE IN EUROPE: Parkinson disease (Orphanet:319705)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000338	Hypomimic face
HP:0000651	Diplopia
HP:0000713	Agitation
HP:0000716	Depression
HP:0000726	Dementia
HP:0000741	Apathy
HP:0000744	Low frustration tolerance
HP:0001268	Mental deterioration
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001337	Tremor
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002120	Cerebral cortical atrophy
HP:0002171	Gliosis
HP:0002172	Postural instability
HP:0002304	Akinesia
HP:0002322	Resting tremor
HP:0002359	Frequent falls
HP:0002360	Sleep disturbance
HP:0002362	Shuffling gait
HP:0002367	Visual hallucination
HP:0002548	Parkinsonism with favorable response to dopaminergic medication
HP:0003394	Muscle spasm
HP:0003581	Adult onset
HP:0004409	Hyposmia
HP:0004926	Orthostatic hypotension due to autonomic dysfunction

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D005910	Glioma	C04.557.465.625.600.380; C04.557.470.670.380; C04.557.580.625.600.380
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D010300	Parkinson Disease	C10.228.140.079.862.500; C10.228.662.600.400; C10.574.928.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2216744 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

3 potent at pChembl≥5 of 6 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.59	Kd	25.61	nM	CHEMBL5653589
7.59	ED50	25.61	nM	CHEMBL5653589
5.24	IC50	5760	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 14 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149772: Binding affinity to human VPS35 incubated for 45 mins by Kinobead based pull down assay	kd	0.0256	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178593: Inhibition of VPS35 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	5.7600	uM

CTD chemical–gene interactions

48 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
sodium arsenite	decreases expression	2
bisphenol S	affects expression, increases expression	2
Nickel	decreases expression, decreases reaction, affects expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
FR900359	affects phosphorylation	1
dicrotophos	decreases expression	1
sodium arsenate	decreases expression	1
titanium dioxide	increases expression	1
pyrogallol 1,3-dimethyl ether	affects localization, affects cotreatment, decreases expression	1
trichostatin A	decreases reaction, affects expression	1
beta-lapachone	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Atrazine	decreases expression	1
Cadmium	increases abundance, increases expression	1
Caffeine	affects phosphorylation	1

ChEMBL screening assays

11 unique, capped per target: 11 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2217171	Binding	Binding affinity to VPS35 in human HepG2 cell lysate after 1 hr by capture compound based LC/MS analysis	Dabigatran and dabigatran ethyl ester: potent inhibitors of ribosyldihydronicotinamide dehydrogenase (NQO2). — J Med Chem

Cellosaurus cell lines

10 cell lines: 5 cancer cell line, 4 induced pluripotent stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C0GD	JUCGRMi001-A	Induced pluripotent stem cell	Male
CVCL_C0GE	JUCGRMi001-B	Induced pluripotent stem cell	Male
CVCL_C0GF	JUCGRMi001-C	Induced pluripotent stem cell	Male
CVCL_D9VP	Ubigene HEK293 VPS35 KO	Transformed cell line	Female
CVCL_TX53	HAP1 VPS35 (-) 1	Cancer cell line	Male
CVCL_TX54	HAP1 VPS35 (-) 2	Cancer cell line	Male
CVCL_TX55	HAP1 VPS35 (-) 3	Cancer cell line	Male
CVCL_TX56	HAP1 VPS35 (-) 4	Cancer cell line	Male
CVCL_TX57	HAP1 VPS35 (-) 5	Cancer cell line	Male
CVCL_YD64	LCSBi001-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

497 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00030979	PHASE4	COMPLETED	Donepezil to Treat Dementia in Parkinson’s Disease
NCT00043849	PHASE4	COMPLETED	Treatment of Agitation/Psychosis in Dementia/Parkinsonism (TAP/DAP)
NCT00095810	PHASE4	COMPLETED	Aripiprazole in Patients With Psychosis Associated With Parkinson’s Disease
NCT00125567	PHASE4	COMPLETED	Stalevo in Early Wearing-Off Patients
NCT00143026	PHASE4	COMPLETED	Study to Compare the Effect of Treatment With Carbidopa/Levodopa/Entacapone on the Quality of Life of Patients With Parkinson’s Disease. This Study is Not Recruiting in the United States
NCT00144300	PHASE4	COMPLETED	Ophthalmologic Safety Study of Pramipexole Immediate Release (IR) Versus Ropinirole in Early Parkinson’s Disease (PD) Patients
NCT00153972	PHASE4	COMPLETED	Dopamine Turnover Rate as Surrogate Parameter for Diagnosis of Early Parkinson’s Disease
NCT00174239	PHASE4	TERMINATED	Study Of Cabaser and Sinemet CR For The Treatment Of Nighttime Symptoms Associated With Parkinson’s Disease.
NCT00215904	PHASE4	COMPLETED	D-serine Adjuvant Treatment for Parkinson’s Disease
NCT00247247	PHASE4	COMPLETED	Comtess® Versus Cabaseril® as Add-on to Levodopa in the Treatment of Parkinsonian Patients Suffering From Wearing- Off.
NCT00272688	PHASE4	COMPLETED	Continuous Delivery of Levodopa in Patients With Advanced Idiopathic Parkinsons Disease - Cost-benefit
NCT00297778	PHASE4	COMPLETED	Pramipexole Versus Placebo in Parkinson’s Disease (PD) Patients With Depressive Symptoms
NCT00304161	PHASE4	COMPLETED	Effectiveness of Antidepressant Treatment for Depression in People With Parkinson’s Disease
NCT00307450	PHASE4	COMPLETED	Efficacy and Safety of Levetiracetam Versus Placebo on Levodopa-induced Dyskinesias in Advanced Parkinson’s Disease
NCT00321854	PHASE4	COMPLETED	Study of (Mirapex) Pramipexole for the Early Treatment of Parkinsons Disease (PD)
NCT00354133	PHASE4	UNKNOWN	Controlled Trial With Deep Brain Stimulation in Patients With Early Parkinson’s Disease
NCT00373087	PHASE4	COMPLETED	COMT Polymorphism and Entacapone Efficacy
NCT00391898	PHASE4	COMPLETED	Efficacy of Levodopa/Carbidopa/Entacapone vs Levodopa/Carbidopa in Parkinson’s Disease Patients With Early Wearing-off
NCT00399477	PHASE4	COMPLETED	A Non-Blinded Study Demonstrating the Effectiveness and Safety of Azilect Alone or in Combination Therapy in Parkinson’s Disease
NCT00402233	PHASE4	COMPLETED	A Randomized, Double-blind, Active (Pramipexole 0.5 mg Tid) and Placebo Controlled, Study of Pramipexole Given 0.5 mg and 0.75 mg Bid Over 12-week Treatment in Early Parkinson’s Disease (PD) Patients
NCT00437125	PHASE4	COMPLETED	Study on the Tolerability of Duloxetine in Depressed Patients With Parkinson’s Disease
NCT00443872	PHASE4	COMPLETED	Efficacy of Orally Disintegrating Selegiline in Parkinson’s Patients Experiencing Adverse Effects With Dopamine Agonists
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00462007	PHASE4	COMPLETED	Study to Evaluate Initiation of Stalevo in Early Wearing-off
NCT00462254	PHASE4	TERMINATED	Ramelteon (ROZEREM) in the Treatment of Sleep Disturbances Associated With Parkinson’s Disease
NCT00477802	PHASE4	TERMINATED	Botulinum Toxin Type A (Botox) in the Management of Levodopa-Induced Peak-Dose Dyskinesias in Parkinson’s Disease
NCT00485069	PHASE4	COMPLETED	REQUIP (Ropinirole Hydrochloride) IR Long-Term Phase 4 Study
NCT00489255	PHASE4	COMPLETED	Safety/Efficacy of Tigan® to Control Nausea/Vomiting Experienced During Apokyn® Initiation and Treatment
NCT00526630	PHASE4	COMPLETED	Methylphenidate for the Treatment of Gait Impairment in Parkinson’s Disease
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT00571285	PHASE4	TERMINATED	Clinical Effects of Vitamin D Repletion in Patients With Parkinson’s Disease
NCT00584025	PHASE4	WITHDRAWN	Keppra IV for the Treatment of Motor Fluctuations in Parkinson’s Disease
NCT00584090	PHASE4	WITHDRAWN	Solifenacin Succinate (VESIcare) for the Treatment of Urinary Incontinence in Parkinson’s Disease
NCT00590122	PHASE4	COMPLETED	Parcopa Versus Carbidopa-levodopa in a Single Dose Cross-over Comparison Study
NCT00594464	PHASE4	COMPLETED	A Trial of Neupro® (Rotigotine Transdermal Patch) in Patients With Parkinson’s Disease Undergoing Surgery
NCT00601978	PHASE4	WITHDRAWN	Carbidopa/Levodopa Versus Carbidopa/Levodopa/Entacapone on Markers of Event Related Potentials (ERPs) in Patients With Idiopathic Parkinson’s Disease (PD) and End-of-dose Wearing Off