PMID- 32722888
OWN - NLM
STAT- MEDLINE
DCOM- 20211122
LR  - 20240226
IS  - 1365-2990 (Electronic)
IS  - 0305-1846 (Linking)
VI  - 47
IP  - 2
DP  - 2021 Feb
TI  - Ataxic phenotype and neurodegeneration are triggered by the impairment of 
      chaperone-mediated autophagy in cerebellar neurons.
PG  - 198-209
LID - 10.1111/nan.12649 [doi]
AB  - AIMS: Chaperone-mediated autophagy (CMA) is a pathway involved in the autophagy 
      lysosome protein degradation system. CMA has attracted attention as a 
      contributing factor to neurodegenerative diseases since it participates in the 
      degradation of disease-causing proteins. We previously showed that CMA is 
      generally impaired in cells expressing the proteins causing spinocerebellar 
      ataxias (SCAs). Therefore, we investigated the effect of CMA impairment on motor 
      function and the neural survival of cerebellar neurons using the micro RNA 
      (miRNA)-mediated knockdown of lysosome-associated protein 2A (LAMP2A), a 
      CMA-related protein. METHODS: We injected adeno-associated virus serotype 9 
      vectors, which express green fluorescent protein (GFP) and miRNA (negative 
      control miRNA or LAMP2A miRNA) under neuron-specific synapsin I promoter, into 
      cerebellar parenchyma of 4-week-old ICR mice. Motor function of mice was 
      evaluated by beam walking and footprint tests. Immunofluorescence experiments of 
      cerebellar slices were conducted to evaluate histological changes in cerebella. 
      RESULTS: GFP and miRNA were expressed in interneurons (satellite cells and basket 
      cells) in molecular layers and granule cells in the cerebellar cortices, but not 
      in cerebellar Purkinje cells. LAMP2A knockdown in cerebellar neurons triggered 
      progressive motor impairment, prominent loss of cerebellar Purkinje cells, 
      interneurons, granule cells at the late stage, and astrogliosis and microgliosis 
      from the early stage. CONCLUSIONS: CMA impairment in cerebellar interneurons and 
      granule cells triggers the progressive ataxic phenotype, gliosis and the 
      subsequent degeneration of cerebellar neurons, including Purkinje cells. Our 
      present findings strongly suggest that CMA impairment is related to the 
      pathogenesis of various SCAs.
CI  - (c) 2020 British Neuropathological Society.
FAU - Sato, Masahiro
AU  - Sato M
AD  - Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical 
      Sciences, Kumamoto University, Kumamoto, Japan.
AD  - Laboratory for Mechanistic Chemistry of Biomolecules, Department of Chemistry, 
      Keio University, Yokohama, Japan.
FAU - Ohta, Tomoko
AU  - Ohta T
AD  - Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical 
      Sciences, Kumamoto University, Kumamoto, Japan.
FAU - Morikawa, Yuri
AU  - Morikawa Y
AD  - Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical 
      Sciences, Kumamoto University, Kumamoto, Japan.
FAU - Konno, Ayumu
AU  - Konno A
AD  - Department of Neurophysiology & Neural Repair, Gunma University Graduate School 
      of Medicine, Maebashi, Japan.
FAU - Hirai, Hirokazu
AU  - Hirai H
AD  - Department of Neurophysiology & Neural Repair, Gunma University Graduate School 
      of Medicine, Maebashi, Japan.
FAU - Kurauchi, Yuki
AU  - Kurauchi Y
AD  - Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical 
      Sciences, Kumamoto University, Kumamoto, Japan.
FAU - Hisatsune, Akinori
AU  - Hisatsune A
AD  - Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical 
      Sciences, Kumamoto University, Kumamoto, Japan.
FAU - Katsuki, Hiroshi
AU  - Katsuki H
AD  - Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical 
      Sciences, Kumamoto University, Kumamoto, Japan.
FAU - Seki, Takahiro
AU  - Seki T
AUID- ORCID: 0000-0002-9894-4768
AD  - Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical 
      Sciences, Kumamoto University, Kumamoto, Japan.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200809
PL  - England
TA  - Neuropathol Appl Neurobiol
JT  - Neuropathology and applied neurobiology
JID - 7609829
RN  - 0 (Lysosomal-Associated Membrane Protein 2)
SB  - IM
MH  - Animals
MH  - Cerebellar Ataxia/metabolism/*pathology
MH  - Cerebellum/metabolism/*pathology
MH  - Chaperone-Mediated Autophagy/*physiology
MH  - Lysosomal-Associated Membrane Protein 2/*metabolism
MH  - Mice, Inbred ICR
MH  - Nerve Degeneration/metabolism/*pathology
MH  - Neurons/metabolism/*pathology
MH  - Phenotype
MH  - Mice
OTO - NOTNLM
OT  - LAMP2A
OT  - cerebellum
OT  - chaperone-mediated autophagy
OT  - gliosis
OT  - motor dysfunction
OT  - neurodegeneration
OT  - spinocerebellar ataxia
EDAT- 2020/07/30 06:00
MHDA- 2021/11/23 06:00
CRDT- 2020/07/30 06:00
PHST- 2020/04/01 00:00 [received]
PHST- 2020/07/13 00:00 [revised]
PHST- 2020/07/15 00:00 [accepted]
PHST- 2020/07/30 06:00 [pubmed]
PHST- 2021/11/23 06:00 [medline]
PHST- 2020/07/30 06:00 [entrez]
AID - 10.1111/nan.12649 [doi]
PST - ppublish
SO  - Neuropathol Appl Neurobiol. 2021 Feb;47(2):198-209. doi: 10.1111/nan.12649. Epub 
      2020 Aug 9.