Presynaptic Dysfunction in Neurons Derived from Tay–Sachs iPSCs

Matsushita, Kozo; Numakawa, Tadahiro; Odaka, Haruki; Kajihara, Ryutaro; Soga, Minami; Ozasa, Shiro; Nakamura, Kimitoshi; Mizuta, Hiroshi; Era, Takumi

doi:10.1016/j.neuroscience.2019.06.026

Cited by 21 publications

(10 citation statements)

References 36 publications

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“…In humans, a well-established NGT-binding protein is the lysosomal enzyme hexosaminidase A (HEXA). HEXA activity is linked to autophagy and mutations in HEXA cause the lysosomal storage disorder Tay-Sachs disease ( Okada and O’Brien, 1969 ; Urbanelli et al, 2014 ; Matsushita et al, 2019 ). HEXA, CLN5, and Dictyostelium Cln5 all have glycoside hydrolase activity ( Okada and O’Brien, 1969 ; Huber and Mathavarajah, 2018a ).…”

Section: Resultsmentioning

confidence: 99%

Aberrant Autophagy Impacts Growth and Multicellular Development in a Dictyostelium Knockout Model of CLN5 Disease

McLaren

Mathavarajah

Kim

et al. 2021

Front. Cell Dev. Biol.

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Mutations in CLN5 cause a subtype of neuronal ceroid lipofuscinosis (NCL) called CLN5 disease. While the precise role of CLN5 in NCL pathogenesis is not known, recent work revealed that the protein has glycoside hydrolase activity. Previous work on the Dictyostelium discoideum homolog of human CLN5, Cln5, revealed its secretion during the early stages of development and its role in regulating cell adhesion and cAMP-mediated chemotaxis. Here, we used Dictyostelium to examine the effect of cln5-deficiency on various growth and developmental processes during the life cycle. During growth, cln5– cells displayed reduced cell proliferation, cytokinesis, viability, and folic acid-mediated chemotaxis. In addition, the growth of cln5– cells was severely impaired in nutrient-limiting media. Based on these findings, we assessed autophagic flux in growth-phase cells and observed that loss of cln5 increased the number of autophagosomes suggesting that the basal level of autophagy was increased in cln5– cells. Similarly, loss of cln5 increased the amounts of ubiquitin-positive proteins. During the early stages of multicellular development, the aggregation of cln5– cells was delayed and loss of the autophagy genes, atg1 and atg9, reduced the extracellular amount of Cln5. We also observed an increased amount of intracellular Cln5 in cells lacking the Dictyostelium homolog of the human glycoside hydrolase, hexosaminidase A (HEXA), further supporting the glycoside hydrolase activity of Cln5. This observation was also supported by our finding that CLN5 and HEXA expression are highly correlated in human tissues. Following mound formation, cln5– development was precocious and loss of cln5 affected spore morphology, germination, and viability. When cln5– cells were developed in the presence of the autophagy inhibitor ammonium chloride, the formation of multicellular structures was impaired, and the size of cln5– slugs was reduced relative to WT slugs. These results, coupled with the aberrant autophagic flux observed in cln5– cells during growth, support a role for Cln5 in autophagy during the Dictyostelium life cycle. In total, this study highlights the multifaceted role of Cln5 in Dictyostelium and provides insight into the pathological mechanisms that may underlie CLN5 disease.

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Section: Resultsmentioning

confidence: 99%

Aberrant Autophagy Impacts Growth and Multicellular Development in a Dictyostelium Knockout Model of CLN5 Disease

McLaren

Mathavarajah

Kim

et al. 2021

Front. Cell Dev. Biol.

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“…S9E). Structural changes of synaptic sites in hippocampal neurons normally occur at the onset of a worsening phenotype and are concomitant with lysosomal enlargement, which is characteristic of overt lysosomal dysfunction [30][31][32][33]. Because of the effect of the observed lysosomal dysfunction on synaptic structure and synaptic function, we examined the ultra-structural changes in the synaptic machinery to identify the relevant structures impacted by the lysosomal dysfunction.…”

Section: The Effects Of Autophagy and Lysosome Dysfunction On Synaptimentioning

confidence: 99%

Ischemia-induced upregulation of autophagy preludes dysfunctional lysosomal storage and associated synaptic impairments in neurons

et al. 2020

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“…Pathogenic variants in the HEXA-encoding gene leads to impaired activity of the enzyme, which loses its ability to cleave the terminal N-acetyl hexosamine residues of fatty acid derivatives known as GM2 gangliosides. As a result, N-acetyl hexosamine residues are massively accumulated in neuronal cells instead of further metabolizing into GM3 gangliosides [2]. Clinical features of the disease include seizures, hypotonia, weakness, regression of motor milestones, maculopathy with 'cherry-red spot', and cognitive deficits.…”

Section: Zusammenfassungmentioning

confidence: 99%

Tay-Sachs Disease: Two Novel Rare HEXA Mutations from Pakistan and Morocco

et al. 2021

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Background Tay-Sachs disease (TSD) is a rare autosomalrecessive genetic disorder characterized by progressive destruction of nerve cells in the brain and spinal cord. It is caused by genetic variations in the HEXA gene leading to a deficiency of β hexosaminidase A (HEXA) isoenzyme activity. This study aimed to identify causative gene variants in 3 unrelated consanguineous families presented with TSD from Pakistan and Morocco. Methods Detailed clinical investigations were carried out on probands in 3 unrelated consanguineous families of Pakistani and Moroccan origin. Targeted gene sequencing and Whole Exome Sequencing (WES) were performed for variant identification. Candidate variants were checked for co-segregation with the phenotype using Sanger sequencing. Public databases including ExAC, GnomAD, dbSNP and the 1,000 Genome Project were searched to determine frequencies of the alleles. Conservation of the missense variants was ensured by aligning orthologous protein sequences from diverse vertebrate species. Results We report on 3 children presented with Tay-Sachs Disease. The β hexosaminidaseA enzyme activity was reduced in the Pakistani patient in one of the pedigrees. Genetic testing revealed 2 novel homozygous variants (p.Asp386Alafs*13 and p.Trp266Gly) in the gene HEXA in Pakistani and Moroccan patients respectively.The third family of Pakistani origin revealed a previously reported variant (p.Tyr427Ilefs*5) in HEXA. p.Tyr427Ilefs*5 is the most commonly occurring pathogenic variationin Ashkenazi but was not reported in Pakistani population. Conclusion Our study further expands the ethnic and mutational spectrum of Tay-Sachs disease emphasizing the usefulness of WES as a powerful diagnostic tool where enzymatic activity is not performed for Tay-Sachs disease. The study recommends targeted screening for these mutations (p.Tyr427Ilefs5) for cost effective testing of TSD patients. Further, the study would assist in carrier testing and prenatal diagnosis of the affected families.

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Presynaptic Dysfunction in Neurons Derived from Tay–Sachs iPSCs

Cited by 21 publications

References 36 publications

Aberrant Autophagy Impacts Growth and Multicellular Development in a Dictyostelium Knockout Model of CLN5 Disease

Aberrant Autophagy Impacts Growth and Multicellular Development in a Dictyostelium Knockout Model of CLN5 Disease

Ischemia-induced upregulation of autophagy preludes dysfunctional lysosomal storage and associated synaptic impairments in neurons

Tay-Sachs Disease: Two Novel Rare HEXA Mutations from Pakistan and Morocco

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