Table 4 Characteristics of pathogenic VCP variants relevant to neurodegeneration. The properties of VCP mutants linked to neurodegeneration are listed. Phenotype descriptions focus on VCP activity, subcellular distribution, and the cellular activities impacted. The changes relative to the wild type protein are listed. Neurodegenerative diseases linked to the VCP mutants are also shown. Not determined, consistent results describing the effects on cellular parameters are not yet available; ?, disease link not defined. ALS, amyotrophic lateral sclerosis; CMT2Y, Charcot-Marie-Tooth disease, type 2y; HSP, hereditary spastic paraplegia; MSP1, multisystem proteinopathy 1; PMA, progressive muscular atrophy, a subtype of ALS. Information was accumulated from ClinVar or other databases [222,223,224] and original papers. VCP mutagenesis identified additional amino acid residues that modulate VCP function [225]. Only mutations linked to neurodegenerative diseases are included in Table 4
VCP variant | Phenotype: changes in cellular parameters | Disease link | References |
|---|---|---|---|
Mutations in N domain (residues 1–187) | |||
 I27V | not determined | MSP1, PD | |
 K60R | not determined | ALS | [228] |
 R89Q | not determined | ALS | [229] |
 N91Y | not determined | ALS- PMA, FTD, ALS, MSP1 | |
 R93C | not determined | MSP1, ALS | |
 R93H | not determined | HSP, FTD, ALS, MSP1 | |
 R95C | not determined | ? | [223] |
 R95G | accelerated substrate unfolding in complex with UFD1L-NPL4; elevated basal ATPase activity; smaller increase in ATPase activity upon substrate binding; imbalanced cofactor binding; reduced nuclear levels; altered ER organization; impaired dendritic spine formation; reduced interaction with Ankrd13A; reduced interaction with caveolin-1 | MSP1 | |
 R95H | not determined | ? | [223] |
 G97E | suppresses VCP hexamer assembly | MSP1, CMTY2, FTD, ALS, atypical MSP1 | |
 D98E | not determined | MSP1 | |
 D98V | not determined | ALS | [229] |
 I114V | not determined | ALS | |
 T127A | not determined | FTD | [234] |
 G128A | not determined | likely pathogenic | |
 P137L | accumulation of autophagosomes | MSP1 | [236] |
 P137S | not determined | AD | |
 I151V | not determined | ALS | [229] |
 R155C | reduced nuclear levels; increased death of spinal cord motor neurons; aberrant synapse formation; altered transcription; ER stress; mitochondrial swelling; reduced mitochondrial membrane potential; reduced ATP production; reduced mitochondrial ATP synthase activity; reduced ADP/ATP translocation across mitochondrial membranes; increased oxidative stress; TDP-43 mislocalized; increased levels of insoluble and phosphorylated TDP-43 in brain; autophagosome-lysosome dysfunction (accumulation of autophagosomes and endolysosomes) | ALS, HSP, ALS- PMA | |
 R155G | not determined | ? | [223] |
 R155H | increased affinity for UFD1L-NPL4; accelerated substrate unfolding in complex with UFD1L-NPL4; elevated basal ATPase activity; smaller increase in ATPase activity upon substrate binding; reduced binding to UBXD1 (UBXN6); imbalanced cofactor binding; reduced nuclear levels; reduced mitochondrial membrane potential; reduced ATP production; excessive degradation of mitofusin; impaired mitochondrial fusion; altered axonal transport of mitochondria (Drosophila ortholog mutant dVCP R152H); deficient lysosomal clearance; reduced interaction with ANKRD13A; reduced interaction with caveolin-1 | MSP1, ALS | |
 R155P | reduced nuclear levels | MSP1, FTD, ALS | |
 R155S | not determined | MSP1, FTD, A:S | [224] |
 G156C | not determined | ALS | [229] |
 G157R | accumulation of autophagosomes | MSP1, FTD, ALS | |
 M158V | increased number of spinal motor neurons with VCP-positive nuclei; increased levels of cytoplasmic TDP-43 | ALS, MSP1, FTD | |
 R159C | VCP- and ubiquitin-positive cytoplasmic and nuclear aggregates in muscle | MSP1 HSP, ALS | |
 R159G | not determined | ALS, ALS-FTD | |
 R159H | accelerated substrate unfolding in complex with UFD1L-NPL4; elevated basal ATPase activity; smaller increase in ATPase activity upon substrate binding; increased cytoplasmic abundance of TDP-43 | MSP1, ALS, FTD | |
 R159S | not determined | ALS | [224] |
 S171R | not determined | CMT2Y | [249] |
 E185K | defective autophagy, accumulation of immature autophagosomes | CMT2Y | [250] |
Mutations in N-D1 linker (residues 188–207) | |||
 R191G | not determined | ALS | [229] |
 R191Q | accelerated substrate unfolding in complex with UFD1L-NPL4; elevated basal ATPase activity; smaller increase in ATPase activity upon substrate binding; reduced nuclear levels; increased cell death; aberrant synapse formation, altered transcription; TDP-43 mislocalized; ER stress; mitochondrial swelling; reduced mitochondrial membrane potential; reduced ATP production; reduced mitochondrial ATP synthase activity; reduced ADP/ATP translocation across mitochondrial membranes; increased oxidative stress | MSP1, ALS, PD, CMT2Y, FTD | |
 R191P | not determined | ALS, FTD | |
 L198W | accelerated substrate unfolding in complex with UFD1L-NPL4; elevated basal ATPase activity; imbalanced cofactor binding; smaller increase in ATPase activity upon substrate binding; cytoplasmic and intranuclear inclusions in muscle; deficient lysosomal clearance | MSP1 | |
Mutations in D1 domain (residues 208–458) | |||
 I216M | not determined | ? | [223] |
 A232E | increased affinity for UFD1L-NPL4; accelerated substrate unfolding in complex with UFD1L-NPL4; elevated basal ATPase activity; imbalanced cofactor binding; smaller increase in ATPase activity upon substrate binding; reduced nuclear levels; excessive degradation of mitofusin; impaired mitochondrial fusion; altered axonal transport of mitochondria (Drosophila ortholog mutant dVCP A229E); ubiquitin- and TDP-43-positive aggregates accumulated in muscle; TDP-43 accumulated in cytoplasm of brain cells; deficient lysosomal clearance; NF-kB activation; reduced interaction with ANKRD13A; reduced interaction with caveolin-1; altered processing of transcription factor SREBP1, changes in lipid biosynthesis | MSP1 | |
 T262A | increased affinity for UFD1L-NPL4; accelerated substrate unfolding in complex with UFD1L-NPL4; elevated basal ATPase activity; smaller increase in ATPase activity upon substrate binding | MSP1, PD | |
 N387H | TDP-43 positive inclusions in muscle | MSP1 | [253] |
 N387T | not determined | ALS | |
 G376E | not determined; likely pathogenic | FTD | [254] |
 D395A | reduced ATPase activity | behavioral FTD | [255] |
 D395G | reduced ATPase activity; accumulation of tau-containing NFTs; increased spread of proteopathic seeds | FTD | |
 A439S | not determined | MSP1 | [259] |
 D450V | not determined | MSP1 | [232] |
Mutations in D2 domain (residues 481–761) | |||
 R487H | not determined | ALS, pyramidal ALS | |
 E578Q | substrate trapping; ATPase activity deficient; ER stress induced; ubiquitinated proteins accumulated at ER membrane; deficient lysosomal clearance | MSP1 | |
 D592N | impaired binding to 20S proteasome subunit | ALS, FTD with neurofibrillary tangles | |
 R662C | not determined | ALS | |
Others | |||
 Splice variant; c.1696-3C > T | not determined | ALS | [228] |