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No symphony without bassoon and piccolo: changes in synaptic active zone proteins in Huntington’s disease
- Source :
- Acta Neuropathologica Communications, Acta Neuropathologica Communications, Vol 8, Iss 1, Pp 1-16 (2020)
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- Prominent features of HD neuropathology are the intranuclear and cytoplasmic inclusions of huntingtin and striatal and cortical neuronal cell death. Recently, synaptic defects have been reported on HD-related studies, including impairment of neurotransmitter release and alterations of synaptic components. However, the definite characteristics of synapse dysfunction and the underlying mechanisms remain largely unknown. We studied the gene expression levels and patterns of a number of proteins forming the cytoskeletal matrix of the presynaptic active zones in HD transgenic mice (R6/1), in hippocampal neuronal cultures overexpressing mutant huntingtin and in postmortem brain tissues of HD patients. To investigate the interactions between huntingtin and active proteins, we performed confocal microscopic imaging and immunoprecipitation in mouse and HEK 293 cell line models. The mRNA and protein levels of Bassoon were reduced in mouse and cell culture models of HD and in brain tissues of patients with HD. Moreover, a striking re-distribution of a complex of proteins including Bassoon, Piccolo and Munc 13–1 from the cytoplasm and synapses into intranuclear huntingtin aggregates with loss of active zone proteins and dendritic spines. This re-localization was age-dependent and coincided with the formation of huntingtin aggregates. Using co-immunoprecipitation, we demonstrated that huntingtin interacts with Bassoon, and that this interaction is likely mediated by a third linking protein. Three structural proteins involved in neurotransmitter release in the presynaptic active zones of neurons are altered in expression and that the proteins are redistributed from their normal functional site into mutant huntingtin aggregates.
- Subjects :
- Adult
Male
0301 basic medicine
Synaptic dysfunction
Dendritic spine
Huntingtin
Dendritic Spines
Gene Expression
Mice, Transgenic
Nerve Tissue Proteins
Protein aggregation
Hippocampus
lcsh:RC346-429
Pathology and Forensic Medicine
Synapse
03 medical and health sciences
Cellular and Molecular Neuroscience
chemistry.chemical_compound
0302 clinical medicine
Huntington's disease
medicine
Animals
Humans
RNA, Messenger
Active zone
Neurotransmitter
lcsh:Neurology. Diseases of the nervous system
Aged
Aged, 80 and over
Huntingtin Protein
Chemistry
Research
Neuropeptides
Middle Aged
medicine.disease
Cell biology
Cytoskeletal Proteins
HEK293 Cells
Huntington Disease
030104 developmental biology
Cytoplasm
Mutation
Synapses
Neurology (clinical)
Active zone proteins
030217 neurology & neurosurgery
Huntington’s disease
Subjects
Details
- ISSN :
- 20515960
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Acta Neuropathologica Communications
- Accession number :
- edsair.doi.dedup.....29f67194bd3d5e82c2ff3859946b201f