Accumulated α-synuclein affects the progression of GM2 gangliosidoses

Suzuki, Kyoko; Yamaguchi, Akira; Yamanaka, Shōji; Kanzaki, Seiichi; Kawashima, Masato; Togo, Takashi; Katsuse, Omi; Koumitsu, Noriko; Aoki, Naoya; Iseki, Eizo; Kosaka, Kenji; Yamaguchi, Kayoko; Hashimoto, Makoto; Aoki, Ichiro; Hirayasu, Yoshio

doi:10.1016/j.expneurol.2016.07.011

Cited by 16 publications

(21 citation statements)

References 46 publications

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“…The findings of the present study correlate in part with those of Suzuki et al . , that is full or partial depletion of endogenous α‐synuclein does not ameliorate primary and secondary substrate accumulation in MPS IIIA mouse brain, as anticipated. However, our findings contrast with those obtained in Sandhoff mice with full α‐synuclein deficiency (α‐synuclein heterozygotes were not examined by Suzuki et al .…”

Section: Discussionsupporting

confidence: 61%

“…More recently, mice with the paediatric‐onset neurodegenerative lysosomal storage disorder Sandhoff disease, when depleted of endogenous α‐synuclein , exhibited improvements in some disease lesions; improved macroautophagy (reduced LC3‐II), reduced numbers of ubiquitin‐positive inclusions and resolution of thalamic microglial activation, plus lower nigral dopaminergic neurone loss, potentially underlying the small but significant improvements in phenotype observed. This is despite the fact that no change to primary substrate accumulation (glycolipid storage) was noted.…”

Section: Discussionmentioning

confidence: 99%

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Early disease course is unaltered in mucopolysaccharidosis type IIIA (MPS IIIA) mice lacking α‐synuclein

Soe

Beard

Neumann

et al. 2019

Neuropathology Appl Neurobio

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2019)Neuropathology and Applied Neurobiology 45, 715-731 Early disease course is unaltered in mucopolysaccharidosis type IIIA (MPS IIIA) mice lacking a-synuclein Background: Sanfilippo syndrome (mucopolysaccharidosis type IIIA; MPS IIIA) is an inherited paediatric-onset neurodegenerative disorder caused by the lysosomal deficiency of sulphamidase with subsequent accumulation of heparan sulphate. The pathological mechanisms responsible for clinical disease are unknown; however, intraneuronal accumulation of aggregation-prone proteins such as a-synuclein, phosphorylated tau and amyloid precursor protein suggests inefficient intracellular trafficking and lysosomal degradation. Aim: To investigate the contribution the accumulating a-synuclein plays in early symptom emergence that is, impaired cognition, reduced anxiety and motor deficits, first detectable between 3-5 months of age. Methods: We have crossed congenic MPS IIIA mice with a-synuclein-deficient (Snca tm1Rosl /J) mice and evaluated phenotype and brain disease lesions. Results: In a battery of behavioural tests performed on mice aged 12-22 weeks, we were unable to differentiate a-synuclein-deficient MPS IIIA mice from those with one or both copies of the a-synuclein gene; all three affected genotypes were significantly impaired in test performance when compared to wildtype littermates. Histological studies revealed that the rate, location and nature of deposition of other proteinaceous lesions, the disruption to endolysosomal protein expression and the inflammatory response seen in the brain of a-synuclein-deficient MPS IIIA mice reflected that seen in MPS IIIA mice homo-or heterozygous for a-synuclein. Conclusion: Deletion and/or deficiency of a-synuclein does not influence clinical and neuropathological disease progression in murine MPS IIIA, demonstrating that in and of itself, this protein does not initiate the cognitive and motor symptoms that occur in the first 5 months of life in MPS IIIA mice.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Early disease course is unaltered in mucopolysaccharidosis type IIIA (MPS IIIA) mice lacking α‐synuclein

Soe

Beard

Neumann

et al. 2019

Neuropathology Appl Neurobio

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“…Collapsing and electrondense mitochondria are also present in the brain of hexosaminidase subunit b ( Hexb ) knockout mice, a model of GM2 gangliosidosis (Suzuki et al . ). Furthermore, neurons from a mouse model of mucopolysaccaridosis III type C show swollen and damaged mitochondria (Martins et al .…”

Section: Mitochondria and Lysosomal Storage Disordersmentioning

confidence: 97%

Mitochondria, lysosomes, and dysfunction: their meaning in neurodegeneration

Audano

Schneider

Mitro

2018

Journal of Neurochemistry

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In the last decades, lysosomes and mitochondria were considered distinct and physically separated organelles involved in different cellular functions. While lysosomes were thought to exclusively be the rubbish dump of the cell involved in the degradation of proteins and other cell compartments, mitochondria were considered solely involved in the oxidation of energy substrate to get ATP, together with other minor duties. Nowadays, our view of these organelles is profoundly changed since studies demonstrated that mitochondria and lysosome are mutually functional, maintaining proper cell homeostasis. Furthermore, the onset of neurodegenerative diseases (i.e., Parkinson's disease, Alzheimer's disease, lysosomal storage disorders, and amyotrophic lateral

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“…The link between defective mitophagy and increased dysfunction of mitochondria has been established also for other lysosomal storage disorders. In particular, mitochondrial alterations have been reported for Gaucher disease [118,119], Niemann-Pick type C1 [120], G M2 gangliosidosis [121], and nephrotic cystinosis [122], indicating that this is a common pathological pathway. A recent study has also shown a severe reduction in autophagic flux in the neurons and astrocytes of a Gaucher disease mouse model [119].…”

Section: Mitochondrial Defects and Oxidative Stressmentioning

confidence: 99%

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

Héon-Roberts

Nguyen

Pshezhetsky

2020

JCM

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The mucopolysaccharidoses (MPS) are a group of diseases caused by the lysosomal accumulation of glycosaminoglycans, due to genetic deficiencies of enzymes involved in their degradation. MPS III or Sanfilippo disease, in particular, is characterized by early-onset severe, progressive neurodegeneration but mild somatic involvement, with patients losing milestones and previously acquired skills as the disease progresses. Despite being the focus of extensive research over the past years, the links between accumulation of the primary molecule, the glycosaminoglycan heparan sulfate, and the neurodegeneration seen in patients have yet to be fully elucidated. This review summarizes the current knowledge on the molecular bases of neurological decline in Sanfilippo disease. It emerges that this deterioration results from the dysregulation of multiple cellular pathways, leading to neuroinflammation, oxidative stress, impaired autophagy and defects in cellular signaling. However, many important questions about the neuropathological mechanisms of the disease remain unanswered, highlighting the need for further research in this area.

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Accumulated α-synuclein affects the progression of GM2 gangliosidoses

Cited by 16 publications

References 46 publications

Early disease course is unaltered in mucopolysaccharidosis type IIIA (MPS IIIA) mice lacking α‐synuclein

Early disease course is unaltered in mucopolysaccharidosis type IIIA (MPS IIIA) mice lacking α‐synuclein

Mitochondria, lysosomes, and dysfunction: their meaning in neurodegeneration

Molecular Bases of Neurodegeneration and Cognitive Decline, the Major Burden of Sanfilippo Disease

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