Elevated VCP ATPase Activity Correlates With Disease Onset in Multisystem Proteinopathy-1

Area of Science:

• Genetics and Molecular Biology
• Neurology
• Biochemistry

Background:

• Multisystem proteinopathy-1 (MSP1) is a late-onset disease caused by over 50 pathogenic variants in p97/VCP.
• MSP1 presents with diverse phenotypes including myopathy, Paget disease, ALS, and FTD, with no established genotype-phenotype correlations.
• The role of VCP intrinsic ATPase activity in MSP1 pathogenesis remains unclear.

Purpose of the Study:

• To identify genotype-phenotype correlations in MSP1.
• To associate these correlations with the intrinsic ATPase activity of VCP.
• To explore potential therapeutic strategies targeting VCP ATPase activity.

Main Methods:

• Patients with MSP1 were identified from literature and a patient registry.
• Age at onset and loss of ambulation were recorded.
• VCP intrinsic ATPase activity was measured using recombinant purified protein.

Main Results:

• Among common VCP variants, R155C showed the earliest average age at onset (38.15 ± 9.78 years).
• Early onset correlated with higher VCP ATPase activity.
• An inverse correlation (r = -0.94, p = 0.01) was found between age at onset and VCP ATPase activity across five variants.

Conclusions:

• In vitro VCP ATPase activity correlates with disease onset in MSP1.
• This correlation may aid in predicting prognosis for patients with known or novel VCP variants.
• Inhibition of VCP ATPase activity presents a potential therapeutic avenue for MSP1.