Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases

Irene Sambri, Rosa D'Alessio, Yulia Ezhova, Teresa Giuliano, Nicolina Cristina Sorrentino, Vincenzo Cacace, Maria De Risi, Mauro Cataldi, Lucio Annunziato, Elvira De Leonibus, Alessandro Fraldi

Research output: Contribution to journalArticlepeer-review

Abstract

Lysosomal storage disorders (LSDs) are inherited diseases characterized by lysosomal dysfunction and often showing a neurodegenerative course. There is no cure to treat the central nervous system in LSDs. Moreover, the mechanisms driving neuronal degeneration in these pathological conditions remain largely unknown. By studying mouse models of LSDs, we found that neurodegeneration develops progressively with profound alterations in presynaptic structure and function. In these models, impaired lysosomal activity causes massive perikaryal accumulation of insoluble α-synuclein and increased proteasomal degradation of cysteine string protein α (CSPα). As a result, the availability of both α-synuclein and CSPα at nerve terminals strongly decreases, thus inhibiting soluble NSF attachment receptor (SNARE) complex assembly and synaptic vesicle recycling. Aberrant presynaptic SNARE phenotype is recapitulated in mice with genetic ablation of one allele of both CSPα and α-synuclein. The overexpression of CSPα in the brain of a mouse model of mucopolysaccharidosis type IIIA, a severe form of LSD, efficiently re-established SNARE complex assembly, thereby ameliorating presynaptic function, attenuating neurodegenerative signs, and prolonging survival. Our data show that neurodegenerative processes associated with lysosomal dysfunction may be presynaptically initiated by a concomitant reduction in α-synuclein and CSPα levels at nerve terminals. They also demonstrate that neurodegeneration in LSDs can be slowed down by re-establishing presynaptic functions, thus identifying synapse maintenance as a novel potentially druggable target for brain treatment in LSDs.

Original languageEnglish
Pages (from-to)112-132
Number of pages21
JournalEMBO Molecular Medicine
Volume9
Issue number1
DOIs
Publication statusPublished - Jan 1 2017

Keywords

  • CSPα
  • lysosomal storage disorders
  • lysosomes
  • neurodegeneration
  • α-synuclein

ASJC Scopus subject areas

  • Molecular Medicine

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