Understanding key to finding cures
Cell organelles known collectively as endolysosomes produce multiple proteins and control cargoes transported around cells. These processes are disrupted in HSP, as well as the processes of ‘waste management’ and recycling within cells.
These are common pathological mechanisms in several diseases and especially in neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and motor neurone disease, as well as HSP. The recurrence of the implication of these pathways in neurodegenerative diseases indicates that the nervous system is particularly sensitive to the disruption of the endolysosomal and autophagic systems.
It remains puzzling why various diseases can occur due to mutations in the same gene. Understanding these mechanisms is critical for future personalized therapeutics
Hereditary spastic paraplegia (HSP) refers to a group of neurological disorders involving the degeneration of motor neurons. Due to their clinical and genetic heterogeneity, finding common effective therapeutics is difficult. Therefore, a better understanding of the common pathological mechanisms is necessary.
The role of several HSP genes/proteins is linked to the endolysosomal and autophagic pathways, suggesting a functional convergence. Furthermore, impairment of these pathways is particularly interesting since it has been linked to other neurodegenerative diseases, which would suggest that the nervous system is particularly sensitive to the disruption of the endolysosomal and autophagic systems.
In this review, we will summarize the involvement of HSP proteins in the endolysosomal and autophagic pathways in order to clarify their functioning and decipher some of the pathological mechanisms leading to HSP.
SOURCE: Cells. 2021 Jul 2;10(7):1678. doi: 10.3390/cells10071678. PMID: 34359848
Current Knowledge of Endolysosomal and Autophagy Defects in Hereditary Spastic Paraplegia
1 Institut du Cerveau-Paris Brain Institute-ICM, INSERM, CNRS, APHP, Sorbonne Université, Pitié-Salpêtrière Hospital, 75013 Paris, France.
2 Neurogenetics Team, EPHE, Paris Sciences Lettres Research University, 75000 Paris, France.