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

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Neurodegenerative diseases often involve protein aggregate deposition in the central nervous system (CNS).
• Protein aggregation in post-mitotic CNS cells leads to cytotoxicity by disrupting cellular functions.
• Genetic factors and aging can influence protein aggregation by impairing cellular degradative functions, notably the autophagy-lysosomal pathway (ALP).

Purpose of the Study:

• To summarize evidence linking autophagy-lysosomal pathway (ALP) dysfunction and protein aggregation in neurodegeneration.
• To focus on lysosomal storage diseases (LSDs) as a model for understanding this interplay.
• To propose a model illustrating the feedback loop between lysosomal defects and protein aggregation.

Main Methods:

• Review of existing literature on neurodegeneration, protein aggregation, and the autophagy-lysosomal pathway.
• Focus on studies related to lysosomal storage diseases (LSDs) and their neurodegenerative aspects.
• Synthesis of findings to propose a mechanistic model.

Main Results:

• Evidence indicates a functional interconnection where ALP dysfunction and protein aggregation induce each other.
• Lysosomal storage diseases (LSDs) exhibit global lysosomal dysfunction and often a severe neurodegenerative course.
• A proposed model suggests inherited lysosomal defects initiate protein aggregation, which further impairs ALP function, creating a detrimental cycle.

Conclusions:

• Inherited lysosomal defects can initiate protein aggregation, exacerbating neurodegeneration.
• The interplay between lysosomal dysfunction and protein aggregation forms a vicious cycle that promotes neurodegenerative cascades.
• Targeting the autophagy-lysosomal pathway may be crucial for managing neurodegenerative processes in LSDs and other conditions.