Multisystem proteinopathy: Where myopathy and motor neuron disease converge

Area of Science:

• Genetics and Molecular Biology
• Neurology
• Pathology

Background:

• Multisystem proteinopathy (MSP) encompasses inherited disorders characterized by neurodegeneration, myopathy, and bone disease.
• Initially identified as inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) linked to VCP gene mutations.
• Recent discoveries implicate additional genes (hnRNPA2B1, hnRNPA1, SQSTM1, MATR3, TIA1, OPTN) in similar phenotypes.

Purpose of the Study:

• To review the spectrum of genes implicated in Multisystem Proteinopathy (MSP).
• To explore the shared molecular pathogenesis, clinical features, and therapeutic strategies for MSP.
• To discuss future research directions for these mechanistically linked disorders.

Main Methods:

• Literature review of genetic mutations and associated phenotypes in MSP.
• Analysis of molecular mechanisms including RNA stress granule function and autophagic degradation.
• Synthesis of current clinical data and standards of care.

Main Results:

• Identification of multiple genes (VCP, hnRNPA2B1, hnRNPA1, SQSTM1, MATR3, TIA1, OPTN) causing MSP.
• Common pathophysiology involves disruption of RNA stress granule dynamics and impaired autophagy.
• Diverse clinical presentations across muscle, nerve, brain, and bone tissues.

Conclusions:

• MSP represents a group of disorders with a common underlying pathophysiology despite genetic heterogeneity.
• Understanding these shared mechanisms is crucial for developing targeted therapies.
• Further research is needed to elucidate specific gene functions and improve patient care.