Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity

He, Li; Li, Shihua; Johnston, Heather; Shelbourne, Peggy

doi:10.1038/78054

Cited by 285 publications

(172 citation statements)

References 25 publications

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“…The Nterminal product generated from caspase cleavage has been shown to associate with synaptic vesicles and inhibit glutamate uptake. 44 Since the binding of full-length Htt to caspase-2 is repeat dependent, an apoptotic initiation event need not occur to start a caspase-dependent amplification process. However, several factors such as lower BDNF levels in HD patients and transgenic mouse models may contribute to a feedback loop of caspase initiation and amplification.…”

Section: Discussionmentioning

confidence: 99%

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

et al. 2004

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Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder resulting in selective neuronal loss and dysfunction in the striatum and cortex. The molecular pathways leading to the selectivity of neuronal cell death in HD are poorly understood. Proteolytic processing of full-length mutant huntingtin (Htt) and subsequent events may play an important role in the selective neuronal cell death found in this disease. Despite the identification of Htt as a substrate for caspases, it is not known which caspase(s) cleaves Htt in vivo or whether regional expression of caspases contribute to selective neuronal cells loss. Here, we evaluate whether specific caspases are involved in cell death induced by mutant Htt and if this correlates with our recent finding that Htt is cleaved in vivo at the caspase consensus site 552. We find that caspase-2 cleaves Htt selectively at amino acid 552. Further, Htt recruits caspase-2 into an apoptosome-like complex. Binding of caspase-2 to Htt is polyglutamine repeat-length dependent, and therefore may serve as a critical initiation step in HD cell death. This hypothesis is supported by the requirement of caspase-2 for the death of mouse primary striatal cells derived from HD transgenic mice expressing full-length Htt (YAC72). Expression of catalytically inactive (dominant-negative) forms of caspase-2, caspase-7, and to some extent caspase-6, reduced the cell death of YAC72 primary striatal cells, while the catalytically inactive forms of caspase-3, -8, and -9 did not. Histological analysis of post-mortem human brain tissue and YAC72 mice revealed activation of caspases and enhanced caspase-2 immunoreactivity in medium spiny neurons of the striatum and the cortical projection neurons when compared to controls. Further, upregulation of caspase-2 correlates directly with decreased levels of brain-derived neurotrophic factor in the cortex and striatum of 3-month YAC72 transgenic mice and therefore suggests that these changes are early events in HD pathogenesis. These data support the involvement of caspase-2 in the selective neuronal cell death associated with HD in the striatum and cortex.

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Section: Discussionmentioning

confidence: 99%

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

et al. 2004

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“…Although mutant huntingtin is widely expressed in neuronal and non-neuronal cells, it preferentially accumulates in striatal neurons and causes neurodegeneration in the brain [1] . This phenomenon has led to extensive studies of mutant huntingtin on neurons.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin prevents the mutant huntingtin-suppressed GLT-1 expression in cultured astrocytes

Chen

Wang

et al. 2012

Acta Pharmacol Sin

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Aim: To investigate the effects of rapamycin on glutamate uptake in cultured rat astrocytes expressing N-terminal 552 residues of mutant huntingtin (Htt-552). Methods: Primary astrocyte cultures were prepared from the cortex of postnatal rat pups. An astrocytes model of Huntington's disease was established using the astrocytes infected with adenovirus carrying coden gene of N-terminal 552 residues of Huntingtin. The protein levels of glutamate transporters GLT-1 and GLAST, the autophagic marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and the autophagy substrate p62 in the astrocytes were examined using Western blotting. The mRNA expression levels of GLT-1 and GLAST in the astrocytes were determined using Real-time PCR. [ 3 H]glutamate uptake by the astrocytes was measured with liquid scintillation counting. Results: The expression of mutant Htt-552 in the astrocytes significantly decreased both the mRNA and protein levels of GLT-1 but not those of GLAST. Furthermore, Htt-552 significantly reduced [ 3 H]glutamate uptake by the astrocytes. Treatment with the autophagy inhibitor 3-MA (10 mmol/L) significantly increased the accumulation of mutant Htt-552, and reduced the expression of GLT-1 and [ 3 H]glutamate uptake in the astrocytes. Treatment with the autophagy stimulator rapamycin (0.2 mg/mL) significantly reduced the accumulation of mutant Htt-552, and reversed the changes in GLT-1 expression and [ 3 H]glutamate uptake in the astrocytes. Conclusion: Rapamcin, an autophagy stimulator, can prevent the suppression of GLT-1 expression and glutamate uptake by mutant Htt-552 in cultured astrocytes.

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“…HD disease symptoms have been reported to arise from neuronal cell loss before nuclear aggregates are detectable but after neuritic aggregates have appeared (6,8). In transgenic mice, the presence of aggregates in neurites correlates with development of neuropathological symptoms (9), and expression of the abnormal protein alters synaptic function (10,11). To explore the mechanisms by which polyQ aggregates may cause neuronal dysfunction, we generated transgenic Drosophila that express the first 548 aa of the human Htt gene with either a pathogenic polyQ tract of 128 repeats (Htt-Q128) or a nonpathogenic tract of 0 repeats (Htt-Q0).…”

mentioning

confidence: 99%

Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease

Lee

Yoshihara

Littleton

2004

Proc. Natl. Acad. Sci. U.S.A.

315

238

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Huntington's disease is an autosomal dominant neurodegenerative disorder caused by expansion of a polyglutamine tract in the huntingtin protein that results in intracellular aggregate formation and neurodegeneration. Pathways leading from polyglutamine tract expansion to disease pathogenesis remain obscure. To elucidate how polyglutamine expansion causes neuronal dysfunction, we generated Drosophila transgenic strains expressing human huntingtin cDNAs encoding pathogenic (Htt-Q128) or nonpathogenic proteins (Htt-Q0). Whereas expression of Htt-Q0 has no discernible effect on behavior, lifespan, or neuronal morphology, pan-neuronal expression of Htt-Q128 leads to progressive loss of motor coordination, decreased lifespan, and time-dependent formation of huntingtin aggregates specifically in the cytoplasm and neurites. Huntingtin aggregates sequester other expanded polyglutamine proteins in the cytoplasm and lead to disruption of axonal transport and accumulation of aggregates at synapses. In contrast, Drosophila expressing an expanded polyglutamine tract alone, or an expanded polyglutamine tract in the context of the spinocerebellar ataxia type 3 protein, display only nuclear aggregates and do not disrupt axonal trafficking. Our findings indicate that nonnuclear events induced by cytoplasmic huntingtin aggregation play a central role in the progressive neurodegeneration observed in Huntington's disease.

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Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity

Cited by 285 publications

References 25 publications

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

Rapamycin prevents the mutant huntingtin-suppressed GLT-1 expression in cultured astrocytes

Cytoplasmic aggregates trap polyglutamine-containing proteins and block axonal transport in a Drosophila model of Huntington's disease

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