Dataset Information

Sil1-Mutant Mice Elucidate Chaperone Function in Neurological Disorders.

ABSTRACT: Chaperone dysfunction leading to the build-up of misfolded proteins could frequently be linked to clinical manifestations also affecting the nervous system and the skeletal muscle. In addition, increase in chaperone function is beneficial to antagonize protein aggregation and thus represents a promising target for therapeutic concepts for many genetic and acquired chaperonopathies. However, little is known on the precise molecular mechanisms defining the cell and tissue abnormalities in the case of impaired chaperone function as well as on underlying effects in the case of compensatory up-regulation of chaperones. This scarcity of knowledge often arises from a lack of appropriate animal models that mimic closely the human molecular, cellular, and histological characteristics. Here, we introduce the Sil1-mutant woozy mouse as a suitable model to investigate molecular and cellular mechanisms of impaired ER-chaperone function affecting the integrity of nervous system and skeletal muscle. The overlapping clinical findings in man and mouse indicate that woozy is a good copy of a human phenotype called Marinesco-Sjögren syndrome. We confirm the presence of ER-stress and expand the biochemical knowledge of altered nuclear envelope in muscle, a hallmark of SIL1-disease. In addition, our data suggest that impaired excitation-contraction coupling might be part of the SIL1-pathophysiology. Our results moreover indicate that divergent expression of pro- and anti-survival proteins is decisive for Purkinje cell survival. By summarizing the current knowledge of woozy, we focus on the suitability of this animal model to study neuroprotective co-chaperone function and to investigate the involvement of co-chaperones in the predisposition of other disorders such as diabetic neuropathy.

SUBMITTER: Buchkremer S

PROVIDER: S-EPMC5271578 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Sil1-Mutant Mice Elucidate Chaperone Function in Neurological Disorders.

Buchkremer Stephan S González Coraspe José Andrés JA Weis Joachim J Roos Andreas A

Journal of neuromuscular diseases 20160501 2

Chaperone dysfunction leading to the build-up of misfolded proteins could frequently be linked to clinical manifestations also affecting the nervous system and the skeletal muscle. In addition, increase in chaperone function is beneficial to antagonize protein aggregation and thus represents a promising target for therapeutic concepts for many genetic and acquired chaperonopathies. However, little is known on the precise molecular mechanisms defining the cell and tissue abnormalities in the case ...[more]

PMID: 27854219

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Project description:We report a broader than previously appreciated clinical spectrum for hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and a potential pathogenic mechanism for DNA methyltransferase (DNMT1) mutations. The clinical presentations and genetic characteristics of nine newly identified HSAN1E kinships (45 affected subjects) were investigated. Five novel mutations of DNMT1 were discovered; p.C353F, p.T481P, p.P491L, p.Y524D and p.I531N, all within the target-sequence domain, and two mutations (p.T481P, p.P491L) arising de novo. Recently, HSAN1E has been suggested as an allelic disorder of autosomal dominant cerebellar ataxia, deafness and narcolepsy. Our results indicate that all the mutations causal for HSAN1E are located in the middle part or N-terminus end of the TS domain, whereas all the mutations causal for autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus end of the TS domain. The impact of the seven causal mutations in this cohort was studied by cellular localization experiments. The binding efficiency of the mutant DNMT proteins at the replication foci and heterochromatin were evaluated. Phenotypic characterizations included electromyography, brain magnetic resonance and nuclear imaging, electroencephalography, sural nerve biopsies, sleep evaluation and neuropsychometric testing. The average survival of HSAN1E was 53.6 years. [standard deviation = 7.7, range 43–75 years], and mean onset age was 37.7 years. (standard deviation = 8.6, range 18–51 years). Expanded phenotypes include myoclonic seizures, auditory or visual hallucinations, and renal failure. Hypersomnia, rapid eye movement sleep disorder and/or narcolepsy were identified in 11 subjects. Global brain atrophy was found in 12 of 14 who had brain MRI. EEGs showed low frequency (delta waves) frontal-predominant abnormality in five of six patients. Marked variability in cognitive deficits was observed, but the majority of patients (89%) developed significant cognitive deficit by the age of 45 years. Cognitive function decline often started with personality changes and psychiatric manifestations. A triad of hearing loss, sensory neuropathy and cognitive decline remains as the stereotypic presentation of HSAN1E. Moreover, we show that mutant DNMT1 proteins translocate to the cytoplasm and are prone to form aggresomes while losing their binding ability to heterochromatin during the G2 cell cycle. Our results suggest mutations in DNMT1 result in imbalanced protein homeostasis through aggresome-induced autophagy. This mechanism may explain why mutations in the sole DNA maintenance methyltransferase lead to selective central and peripheral neurodegeneration.

Project description:We report a broader than previously appreciated clinical spectrum for hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and a potential pathogenic mechanism for DNA methyltransferase (DNMT1) mutations. The clinical presentations and genetic characteristics of nine newly identified HSAN1E kinships (45 affected subjects) were investigated. Five novel mutations of DNMT1 were discovered; p.C353F, p.T481P, p.P491L, p.Y524D and p.I531N, all within the target-sequence domain, and two mutations (p.T481P, p.P491L) arising de novo. Recently, HSAN1E has been suggested as an allelic disorder of autosomal dominant cerebellar ataxia, deafness and narcolepsy. Our results indicate that all the mutations causal for HSAN1E are located in the middle part or N-terminus end of the TS domain, whereas all the mutations causal for autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus end of the TS domain. The impact of the seven causal mutations in this cohort was studied by cellular localization experiments. The binding efficiency of the mutant DNMT proteins at the replication foci and heterochromatin were evaluated. Phenotypic characterizations included electromyography, brain magnetic resonance and nuclear imaging, electroencephalography, sural nerve biopsies, sleep evaluation and neuropsychometric testing. The average survival of HSAN1E was 53.6 years. [standard deviation = 7.7, range 43-75 years], and mean onset age was 37.7 years. (standard deviation = 8.6, range 18-51 years). Expanded phenotypes include myoclonic seizures, auditory or visual hallucinations, and renal failure. Hypersomnia, rapid eye movement sleep disorder and/or narcolepsy were identified in 11 subjects. Global brain atrophy was found in 12 of 14 who had brain MRI. EEGs showed low frequency (delta waves) frontal-predominant abnormality in five of six patients. Marked variability in cognitive deficits was observed, but the majority of patients (89%) developed significant cognitive deficit by the age of 45 years. Cognitive function decline often started with personality changes and psychiatric manifestations. A triad of hearing loss, sensory neuropathy and cognitive decline remains as the stereotypic presentation of HSAN1E. Moreover, we show that mutant DNMT1 proteins translocate to the cytoplasm and are prone to form aggresomes while losing their binding ability to heterochromatin during the G2 cell cycle. Our results suggest mutations in DNMT1 result in imbalanced protein homeostasis through aggresome-induced autophagy. This mechanism may explain why mutations in the sole DNA maintenance methyltransferase lead to selective central and peripheral neurodegeneration.

Project description:BackgroundLoss of fine motor skills is observed in many neurological diseases, and remote monitoring assessments can aid in early diagnosis and intervention. Hand function can be regularly assessed to monitor loss of fine motor skills in people with central nervous system disorders; however, there are challenges to in-clinic assessments. Remotely assessing hand function could facilitate monitoring and supporting of early diagnosis and intervention when warranted.ObjectiveRemote assessments can facilitate the tracking of limitations, aiding in early diagnosis and intervention. This study aims to systematically review existing evidence regarding the remote assessment of hand function in populations with chronic neurological dysfunction.MethodsPubMed and MEDLINE, CINAHL, Web of Science, and Embase were searched for studies that reported remote assessment of hand function (ie, outside of traditional in-person clinical settings) in adults with chronic central nervous system disorders. We excluded studies that included participants with orthopedic upper limb dysfunction or used tools for intervention and treatment. We extracted data on the evaluated hand function domains, validity and reliability, feasibility, and stage of development.ResultsIn total, 74 studies met the inclusion criteria for Parkinson disease (n=57, 77% studies), stroke (n=9, 12%), multiple sclerosis (n=6, 8%), spinal cord injury (n=1, 1%), and amyotrophic lateral sclerosis (n=1, 1%). Three assessment modalities were identified: external device (eg, wrist-worn accelerometer), smartphone or tablet, and telerehabilitation. The feasibility and overall participant acceptability were high. The most common hand function domains assessed included finger tapping speed (fine motor control and rigidity), hand tremor (pharmacological and rehabilitation efficacy), and finger dexterity (manipulation of small objects required for daily tasks) and handwriting (coordination). Although validity and reliability data were heterogeneous across studies, statistically significant correlations with traditional in-clinic metrics were most commonly reported for telerehabilitation and smartphone or tablet apps. The most readily implementable assessments were smartphone or tablet-based.ConclusionsThe findings show that remote assessment of hand function is feasible in neurological disorders. Although varied, the assessments allow clinicians to objectively record performance in multiple hand function domains, improving the reliability of traditional in-clinic assessments. Remote assessments, particularly via telerehabilitation and smartphone- or tablet-based apps that align with in-clinic metrics, facilitate clinic to home transitions, have few barriers to implementation, and prompt remote identification and treatment of hand function impairments.

Dataset Information

Sil1-Mutant Mice Elucidate Chaperone Function in Neurological Disorders.

Publications

Sil1-Mutant Mice Elucidate Chaperone Function in Neurological Disorders.

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