Protein Aggregation and Dysfunction of Autophagy-Lysosomal Pathway: A Vicious Cycle in Lysosomal Storage Diseases.

Antonio Monaco,Alessandro Fraldi

doi:10.3389/fnmol.2020.00037

Abstract

Many neurodegenerative conditions are characterized by the deposition of protein aggregates (mainly amyloid-like) in the central nervous system (CNS). In post-mitotic CNS cells protein aggregation causes cytotoxicity by interfering with various cellular functions. Mutations in different genes may directly cause protein aggregation. However, genetic factors together with aging may contribute to the onset of protein aggregation also by affecting cellular degradative functions, in particular the autophagy-lysosomal pathway (ALP). Increasing body of evidence show that ALP dysfunction and protein aggregation are functionally interconnected and induce each other during neurodegenerative processes. We will summarize the findings supporting these concepts by focusing on lysosomal storage diseases (LSDs), a class of metabolic inherited conditions characterized by global lysosomal dysfunction and often associated to a severe neurodegenerative course. We propose a model by which the inherited lysosomal defects initiate aggregate-prone protein deposition, which, in turns, worsen ALP degradation function, thus generating a vicious cycle, which boost neurodegenerative cascades.

Highlights

Many neurodegenerative conditions are characterized by the deposition of protein aggregates in the central nervous system (CNS)
Alzheimer’s disease (AD), the most common neurodegenerative disorder is characterized by deposition of amyloid plaques, whose main component is the amyloid-beta (Aβ) protein (Goedert and Spillantini, 2006). α-Synuclein accumulation and aggregation within Lewy bodies and neurites of the CNS in the form of amyloid fibrils plays a central role in the pathophysiology of Parkinson’s disease (PD) and in a subset of neurodegenerative conditions known as dementias with Lewy bodies (Spillantini et al, 1997)
Autophagy-lysosomal pathway decline may be caused by genetic factors (LOF – mutations inherited in a dominant or recessive fashion), environmental factors which are known to impact on degradative capability of cells (Nixon et al, 2008) or by protein aggregation itself

Summary

Introduction

Many neurodegenerative conditions are characterized by the deposition of protein aggregates (mainly amyloid-like) in the central nervous system (CNS). We propose a model by which the inherited lysosomal defects initiate aggregate-prone protein deposition, which, in turns, worsen ALP degradation function, generating a vicious cycle, which boost neurodegenerative cascades.

Results

Conclusion