title: Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases.
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.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Sambri
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: D'Alessio
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Ezhova
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Giuliano
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Nicolina Cristina
authors.initials: NC
authors.lastname: Sorrentino
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cacace
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.|Institute of Genetics and Biophysics, National Research Council, Naples, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: De Risi
authors.affiliation: Department of Neuroscience, Reproductive and Odontostomatological Sciences Federico II University, Naples, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Cataldi
authors.affiliation: Department of Neuroscience, Reproductive and Odontostomatological Sciences Federico II University, Naples, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Annunziato
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy.|Institute of Genetics and Biophysics, National Research Council, Naples, Italy.
authors.forename: Elvira
authors.initials: E
authors.lastname: De Leonibus
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy fraldi@tigem.it.
authors.forename: Alessandro
authors.identifier: 0000-0002-7795-0720
authors.initials: A
authors.lastname: Fraldi
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D050956:HSP40 Heat-Shock Proteins / Q000032:analysis*; D016464:Lysosomal Storage Diseases / Q000473:pathology*; D008565:Membrane Proteins / Q000032:analysis*; D051379:Mice; D019636:Neurodegenerative Diseases / Q000473:pathology*; D017729:Presynaptic Terminals / Q000473:pathology*; D059748:Proteolysis; D050600:SNARE Proteins / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism; D051844:alpha-Synuclein / Q000032:analysis*
chemical_list: D050956:HSP40 Heat-Shock Proteins; D008565:Membrane Proteins; D050600:SNARE Proteins; D051844:alpha-Synuclein; C088460:cysteine string protein
keywords: CSPα; lysosomal storage disorders; lysosomes; neurodegeneration; α‐synuclein