Mutations in DNAJC5, Encoding Cysteine-String Protein Alpha, Cause Autosomal-Dominant Adult-Onset Neuronal Ceroid Lipofuscinosis

Nosková, Lenka; Stránecký, Viktor; Hartmannová, Hana; Přistoupilová, Anna; Barešová, Veronika; Ivánek, Robert; Hůlková, Helena; Jahnová, Helena; Zee, Julie van der; Staropoli, John F.; Sims, Katherine B.; Tyynelä, Jaana; Broeckhoven, Christine Van; Nijssen, Peter C.G.; Mole, Sara; Elleder, M; Kmoch, Stanislav

doi:10.1016/j.ajhg.2011.09.003

Cited by 43 publications

(76 citation statements)

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“…a-Synuclein is known to modulate synaptic pathology in mice, at least in part through interactions with another synaptic protein, CSP-a (Chandra et al 2005). Mutations in CSP-a lead to a dominant adult form of NCL, Kuf's disease (CLN4 (Noskov a et al 2011;Benitez et al 2011)), and levels of CSP-a were also significantly modified in synapses from affected regions of CLN5 sheep brain. Similar links have been established for many of the other proteins we examined in our study, where previous data from a combined mouse/Drosophila study identified them as potential regulators of synaptic and axonal degeneration (Wishart et al 2012).…”

Section: Discussionmentioning

confidence: 99%

“…For example, a spontaneous genetic mutation that robustly delays synaptic degeneration (known as Wld S ) can ameliorate neurodegeneration across a range of conditions, including some forms of motor neuron disease (Ferri et al 2003), Parkinson's disease (Sajadi et al 2004) and following global cerebral ischemia (Gillingwater et al 2004) or traumatic brain injury . Furthermore, at the molecular level, a number of individual synaptic proteins that can modulate synaptic vulnerability and degeneration in response to a variety of pathological stimuli have recently been identified, including CSP alpha/DNAJC5 (Fern andez-Chac on Garc ıa-Junco-Clemente et al 2010;Noskov a et al 2011;Wishart et al 2012;Kashyap et al 2014).…”

Section: Introductionmentioning

confidence: 99%

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Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

et al. 2015

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AimsSynapses represent a major pathological target across a broad range of neurodegenerative conditions. Recent studies addressing molecular mechanisms regulating synaptic vulnerability and degeneration have relied heavily on invertebrate and mouse models. Whether similar molecular neuropathological changes underpin synaptic breakdown in large animal models and in human patients with neurodegenerative disease remains unclear. We therefore investigated whether molecular regulators of synaptic pathophysiology, previously identified in Drosophila and mouse models, are similarly present and modified in the brain of sheep with CLN5 Batten disease.MethodsGross neuropathological analysis of CLN5 Batten disease sheep and controls was used alongside postmortem MRI imaging to identify affected brain regions. Synaptosome preparations were then generated and quantitative fluorescent Western blotting used to determine and compare levels of synaptic proteins.ResultsThe cortex was particularly affected by regional neurodegeneration and synaptic loss in CLN5 sheep, whilst the cerebellum was relatively spared. Quantitative assessment of the protein content of synaptosome preparations revealed significant changes in levels of seven out of eight synaptic neurodegeneration proteins investigated in the motor cortex, but not cerebellum, of CLN5 sheep (α‐synuclein, CSP‐α, neurofascin, ROCK2, calretinin, SIRT2, and UBR4).ConclusionsSynaptic pathology is a robust correlate of region‐specific neurodegeneration in the brain of CLN5 sheep, driven by molecular pathways similar to those reported in Drosophila and rodent models. Thus, large animal models, such as sheep, represent ideal translational systems to develop and test therapeutics aimed at delaying or halting synaptic pathology for a range of human neurodegenerative conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular neuropathology of the synapse in sheep with CLN5 Batten disease

et al. 2015

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“…In humans, mutations in the DNAJC5 gene encoding CSPα that produce heterozygous CSPα point mutations or point deletions cause autosomal-dominant, adult onset neuronal ceroid lipofusinosis (ANCL), a neurodegenerative disorder characterized by accumulation of lysosomal cellular debris (Benitez et al, 2011; Nosková et al, 2011; Velinov et al, 2012). Disease onset is between 20–30 years of age and the course and outcome of ANCL involves, increased anxiety, speech difficulties, ataxia, involuntary movements, seizures, cognitive deterioration, dementia with a shortened life expectancy.…”

Section: One J Protein: the Total Protection Planmentioning

confidence: 99%

“…On the other hand, while CSPα L116Δ and CSPα L115R increase BK channel density at the membrane, the increase is not as large as that observed with CSPα HPD-AAA (Kyle et al, 2013), suggesting that CSPα L116Δ and CSPα LL115R are partial loss-of-function mutants. In humans, deletion of residue 116 or replacement of Lys115 by Arg in the cysteine string region results in ANCL (Benitez et al, 2011; Nosková et al, 2011; Velinov et al, 2012), however the mechanism(s) underlying disease pathology is not known. It is becoming increasingly clear that changes in the cysteine string region can promote oligomerization.…”

Section: Presynaptic Ion Channels: Channel Proteostasis and Multi-promentioning

confidence: 99%

CSPÎ±â€”chaperoning presynaptic proteins

Donnelier

Braun

2014

Front. Cell. Neurosci.

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Synaptic transmission relies on precisely regulated and exceedingly fast protein-protein interactions that involve voltage-gated channels, the exocytosis/endocytosis machinery as well as signaling pathways. Although we have gained an ever more detailed picture of synaptic architecture much remains to be learned about how synapses are maintained. Synaptic chaperones are “folding catalysts” that preserve proteostasis by regulating protein conformation (and therefore protein function) and prevent unwanted protein-protein interactions. Failure to maintain synapses is an early hallmark of several degenerative diseases. Cysteine string protein (CSPα) is a presynaptic vesicle protein and molecular chaperone that has a central role in preventing synaptic loss and neurodegeneration. Over the past few years, a number of different “client proteins” have been implicated as CSPα substrates including voltage-dependent ion channels, signaling proteins and proteins critical to the synaptic vesicle cycle. Here we review the ion channels and synaptic protein complexes under the influence of CSPα and discuss gaps in our current knowledge.

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“…The NCLs are the most common group of neurodegenerative diseases in childhood and their clinical course includes progressive mental and psychomotor retardation, epilepsy, blindness and premature death [1]. Currently, nine human NCL genes have been identified: PPT1 (CLN1), TPP1 (CLN2), CLN3, CLN5, CLN6, MFSD8 (CLN7), CLN8, CTSD (CLN10) and DNAJC5 (adult onset NCL) [2][3][4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%