The malin–laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin–proteasome system

Garyali, Punitee; Siwach, Pratibha; Singh, Pankaj Kumar; Puri, Rajat; Mittal, Shucchi; Sengupta, Suman; Parihar, Rashmi; Ganesh, Subramaniam

doi:10.1093/hmg/ddn398

Cited by 110 publications

(101 citation statements)

References 52 publications

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“…55 Important to protein metabolism in neurodegenerative diseases, the laforin-malin complex can suppress cytotoxicity and accumulation of aggregate-prone proteins by interaction with the chaperone proteins, heat-shock protein 70 and C-terminus of Hsc70-interacting protein, to effectively shuttle target proteins to degradation via the proteasome. [56][57][58] Linking LD to autophagy, a recent study provided evidence for a role of laforin in the regulation of autophagy, potentially through the mTOR pathway. 59 In laforin-deficient fibroblasts obtained from patients and in mouse embryonic fibroblasts and liver tissue derived from laforin knockout mice, the levels of the autophagosome marker LC3-II were significantly reduced, indicating compromised autophagosome formation.…”

Section: Autophagy In Pediatric Brain Diseasesmentioning

confidence: 99%

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

et al. 2013

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Pediatric neurodegenerative diseases are a heterogeneous group of diseases that result from specific genetic and biochemical defects. In recent years, studies have revealed a wide spectrum of abnormal cellular functions that include impaired proteolysis, abnormal lipid trafficking, accumulation of lysosomal content, and mitochondrial dysfunction. Within neurons, elaborated degradation pathways such as the ubiquitin-proteasome system and the autophagy-lysosomal pathway are critical for maintaining homeostasis and normal cell function. Recent evidence suggests a pivotal role for autophagy in major adult and pediatric neurodegenerative diseases. We herein review genetic, pathological, and molecular evidence for the emerging link between autophagy dysfunction and lysosomal storage disorders such as Niemann-Pick type C, progressive myoclonic epilepsies such as Lafora disease, and leukodystrophies such as Alexander disease. We also discuss the recent discovery of genetically deranged autophagy in Vici syndrome, a multisystem disorder, and the implications for the role of autophagy in development and disease. Deciphering the exact mechanism by which autophagy contributes to disease pathology may open novel therapeutic avenues to treat neurodegeneration. To this end, an outlook on novel therapeutic approaches targeting autophagy concludes this review. P ediatric neurodegenerative diseases are a heterogeneous group of diseases that result from specific genetic and biochemical defects. Although the age of onset and the clinical course are variable, neurodegenerative disorders of childhood are characterized by progressive neurologic and cognitive dysfunction with loss of speech, vision, hearing, and motor skills, and a frequent association with seizures, feeding difficulties, and failure to thrive. The degenerative process can affect white and gray matter and spreads in a disease-specific manner. Current genetic and biochemical testing and neuroimaging can establish a diagnosis. The outcome for most diseases, however, is still poor, as therapeutic approaches are limited.Accumulation of proteins, polysaccharides, and lipids are common mechanisms shared by major adult-onset neurodegenerative diseases 1-3 and many neurodegenerative diseases of childhood. 4 These conditions are, therefore, often referred to as "storage diseases" or "proteinopathies. " Cells and postmitotic cells such as neurons, in particular, rely on effective cargo targeting, tagging, transportation, and degradation to maintain intracellular homeostasis under normal conditions and metabolic stress. Within this network, autophagy plays an indispensible role by eliminating misfolded and aggregated proteins, lipids, saccharides, and damaged organelles. Recent evidence suggests that autophagy is dysregulated in a number of pediatric neurodegenerative and metabolic diseases. AUTOPHAGY: AN OVERVIEWAutophagy describes intracellular pathways that converge into degradation of target material in lysosomes. 5 The route of cargo delivery to the lysosome distinguishes th...

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Section: Autophagy In Pediatric Brain Diseasesmentioning

confidence: 99%

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

et al. 2013

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“…Laforin also promotes autophagy by inhibiting the mammalian target of rapamycin (mTOR) pathway by a currently unknown mechanism to further protect cells from ER stress [25]. In addition to targeting genes involved in glycogen metabolism, recruitment of Malin further promotes ubiquitination of misfolded and aggregated proteins, thereby facilitating their proteosomal degradation [27]. Laforin also interacts with heat shock factor 1 (HSF1), an essential transcription factor in the heat shock response [26] and is necessary for upregulation of HSF1-dependent gene expression and for protection from thermal stress in COS7 cells [26].…”

Section: Atypical Dusps Currently Implicated In Cancer 21 Laforinmentioning

confidence: 99%

Emerging Roles of Atypical Dual Specificity Phosphatases in Cancer

Cain¹,

Beeser²

2013

Oncogene and Cancer - From Bench to Clinic

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“…10 The polyQ protein ataxin-1 is a soluble protein of about 816 amino acids, which varies depending on the length of polyQ repeats, and located both in the cytoplasm and nucleus. Although the exact functions are not completely understood, ataxin-1 is apparently involved in transcription regulation through its ability to interact with several transcription factors as well as RNA.…”

mentioning

confidence: 99%

Interaction Between DUSP8 and the Polyglutamine Protein Ataxin-1

Lee¹,

Cho

2013

Bulletin of the Korean Chemical Society

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Polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by the expansion of polyQ repeats in the disease proteins. Expansion of polyQ repeats presumably leads to misfolding and aggregation of polyQ proteins.1 Although details of the molecular mechanisms are still elusive, transcriptional dysfunction and oxidative damage are suggested as underlying events responsible for polyQ pathogenesis.2 Misfolded polyQ proteins are frequently concentrated into intranuclear inclusions, which increase generation of reactive oxygen species (ROS) and activate stress signaling pathways. In cultured cells expressing expanded polyQ proteins, mitogen-activated protein kinases (MAPK), e.g., p38 and JNK, are activated and the cytotoxicity induced by polyQ proteins, partially through sustained activation of MAP kinases, can be reduced by administration of a p38 inhibitor.3-6 MAPK are activated by MAPK kinase (MEK)-mediated phosphorylation of threonine and tyrosine residues located in the signature sequence (TxY) and MEK is in turn activated by MAPK kinase kinase (MEKK).7 Since MAPK are involved in a wide variety of cellular processes including cell survival and apoptosis, cells must tightly regulate the magnitude and duration of MAPK activation. The negative regulation of MAPK is often achieved by phosphatase-mediated dephosphorylation of MAPK. A group of protein phosphatases referred as type I cysteinebased protein tyrosine phosphatases including DUSPs (dualspecificity phosphatases) dephosphorylate both tyrosine and serine/threonine residues within the same substrate and as a result counteract MAPK. 8Involvement of protein tyrosine phosphatases (PTPs) in polyQ-induced cell death has been reported in previous studies. Several PTP proteins including MKP-1 are up-regulated by over-expression of cytotoxic polyQ-expanded huntingtin (Htt) fragment.9 Moreover, polyQ-expanded Htt fragment activates JNK pathway by reducing solubility of JNK phosphatase M3/6 (also known as hVH5 or DUSP8). 4A recent study demonstrated that a DUSP protein laforin can suppress the cytotoxicity caused by misfolded proteins and hinted that phosphatases can be potential targets for pharmacological intervention of neurodegenerative disorders.10 The polyQ protein ataxin-1 is a soluble protein of about 816 amino acids, which varies depending on the length of polyQ repeats, and located both in the cytoplasm and nucleus. Although the exact functions are not completely understood, ataxin-1 is apparently involved in transcription regulation through its ability to interact with several transcription factors as well as RNA.11 While it is generally assumed that expansion of polyQ repeats causes misfolding of ataxin-1 and leads to neuronal death in spinocerebellar ataxia 1 (SCA1), contribution of other domains to pathogenesis also becomes increasingly clear. Besides N-terminal polyQ region, AXH domain (570-689; for interaction with transcription factors and RNA), endogenous phosphorylation site (776) and nuclear localization signal (795-798) a...

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The malin–laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin–proteasome system

Cited by 110 publications

References 52 publications

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

Emerging Roles of Atypical Dual Specificity Phosphatases in Cancer

Interaction Between DUSP8 and the Polyglutamine Protein Ataxin-1

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