Endocytic pathways of pathogenic protein aggregates in neurodegenerative diseases

Abstract

Endocytosis is the fundamental uptake process through which cells internalize extracellular materials and species. Neurodegenerative diseases (NDs) are characterized by a progressive accumulation of intrinsically disordered protein species, leading to neuronal death. Misfolding in many proteins leads to various NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and other disorders. Despite the significance of disordered protein species in neurodegeneration, their spread between cells and the cellular uptake of extracellular species is not entirely understood. This review discusses the major internalization mechanisms of the different conformer species of these proteins and their endocytic mechanisms. We briefly introduce the broad types of endocytic mechanisms found in cells and then summarize what is known about the endocytosis of monomeric, oligomeric and aggregated conformations of tau, Aβ, α‐Syn, Huntingtin, Prions, SOD1, TDP‐43 and other proteins associated with neurodegeneration. We also highlight the key players involved in internalizing these disordered proteins and the several techniques and approaches to identify their endocytic mechanisms. Finally, we discuss the obstacles involved in studying the endocytosis of these protein species and the need to develop better techniques to elucidate the uptake mechanisms of a particular disordered protein species.

Novel Ultrasound-Responsive Amyloid Formulation

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Secondary glaucoma: Toward interventions based on molecular underpinnings

“…Once internalized, the aberrant cargo is targeted to lysosomes for degradation and recycling. Impaired endocytosis has been implicated in various neurodegenerative diseases, such as Parkinson, AD, Huntington, and Creutzfeldt-Jakob diseases, all of which, like PEX, share protein aggregate accumulation in the extracellular space as a hallmark feature (Hivare et al, 2023;Ravikumar et al, 2008). Endocytosis and autophagy share pathways and have a common endpoint at the lysosome, where degradation occurs (Lamb et al, 2013).…”

The Biological Activity of Ganoderma lucidum on Neurodegenerative Diseases: The Interplay between Different Active Compounds and the Pathological Hallmarks

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