Biallelic
            <i>SQSTM1</i>
            mutations in early-onset, variably progressive neurodegeneration

Muto, Valentina; Flex, Elisabetta; Kupchinsky, Zachary A.; Primiano, Guido; Galehdari, Hamid; Dehghani, Mohammadreza; Cecchetti, Serena; Carpentieri, Giovanna; Rizza, Teresa; Mazaheri, Neda; Sedaghat, Alireza; Mehrjardi, Mohammad Yahya Vahidi; Traversa, Alice; Nottia, Michela Di; Kousi, Maria; Jamshidi, Yalda; Ciolfi, Andrea; Caputo, Viviana; Malamiri, Reza Azizi; Pantaleoni, Francesca; Martinelli, Simone; Jeffries, Aaron R.; Zeighami, Jawaher; Sherafat, Amir; Giuda, Daniela Di; Shariati, Gholamreza; Carrozzo, Rosalba; Katsanis, Nicholas; Maroofian, Reza; Servidei, Serenella; Tartaglia, Marco

doi:10.1212/wnl.0000000000005869

Cited by 43 publications

(40 citation statements)

References 41 publications

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“…In humans, loss of p62 leads to a childhood-onset neurodegenerative disease with no organs affected other than the central nervous system (Haack et al., 2016, Muto et al., 2018). We therefore sought to study the role of p62 and reprogrammed fibroblasts from two patients carrying a nonsense mutation at the 5′ end of SQSTM1 (p.Arg96 ∗ , patients II:1 and II:4 from family 4 in Haack et al., 2016) to induced pluripotent stem cells (iPSCs), before differentiating them further to neuroepithelial-like stem cells (Pat1 NES or Pat2 NES ) (for details see Experimental Procedures and Falk et al., 2012, Koch et al., 2009).…”

Section: Resultsmentioning

confidence: 99%

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SQSTM1/p62-Directed Metabolic Reprogramming Is Essential for Normal Neurodifferentiation

et al. 2019

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Summary Neurodegenerative disorders are an increasingly common and irreversible burden on society, often affecting the aging population, but their etiology and disease mechanisms are poorly understood. Studying monogenic neurodegenerative diseases with known genetic cause provides an opportunity to understand cellular mechanisms also affected in more complex disorders. We recently reported that loss-of-function mutations in the autophagy adaptor protein SQSTM1/p62 lead to a slowly progressive neurodegenerative disease presenting in childhood. To further elucidate the neuronal involvement, we studied the cellular consequences of loss of p62 in a neuroepithelial stem cell (NESC) model and differentiated neurons derived from reprogrammed p62 patient cells or by CRISPR/Cas9-directed gene editing in NESCs. Transcriptomic and proteomic analyses suggest that p62 is essential for neuronal differentiation by controlling the metabolic shift from aerobic glycolysis to oxidative phosphorylation required for neuronal maturation. This shift is blocked by the failure to sufficiently downregulate lactate dehydrogenase expression due to the loss of p62, possibly through impaired Hif-1α downregulation and increased sensitivity to oxidative stress. The findings imply an important role for p62 in neuronal energy metabolism and particularly in the regulation of the shift between glycolysis and oxidative phosphorylation required for normal neurodifferentiation.

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Section: Resultsmentioning

confidence: 99%

“…Magnetic resonance imaging revealed atrophy of the cerebellum and the vermis cerebelli (Haack et al., 2016). Eleven more patients, with similar clinical presentations, have since been reported (Muto et al., 2018). Nevertheless, there was no clear indication of the pathogenetic mechanism leading to the clinical observations.…”

Section: Introductionmentioning

confidence: 99%

SQSTM1/p62-Directed Metabolic Reprogramming Is Essential for Normal Neurodifferentiation

et al. 2019

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“…P62 is a cytosolic, multi-domain protein, considered to be involved in, among others, selective autophagy [108]. Patients with bi-allelic null mutations in p62 present with childhood-or adolescence-onset neurodegenerative disorder, characterised by progressive gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline [109,110]. Loss of p62 in NES cells resulted in a dramatic increase of LDHA expression, which correlated with deficient neurodifferentiation [99].…”

Section: The Metabolic Switch In Neurogenesismentioning

confidence: 99%

Metabolic regulation of neurodifferentiation in the adult brain

Maffezzini

Calvo‐Garrido

Wredenberg

et al. 2020

Cell. Mol. Life Sci.

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Understanding the mechanisms behind neurodifferentiation in adults will be an important milestone in our quest to identify treatment strategies for cognitive disorders observed during our natural ageing or disease. It is now clear that the maturation of neural stem cells to neurones, fully integrated into neuronal circuits requires a complete remodelling of cellular metabolism, including switching the cellular energy source. Mitochondria are central for this transition and are increasingly seen as the regulatory hub in defining neural stem cell fate and neurodevelopment. This review explores our current knowledge of metabolism during adult neurodifferentiation.

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“…p62 serves as an adaptor protein for autophagic cargo and may facilitate the perinuclear clustering of damaged mitochondria which might facilitate their turnover through autophagy. Investigations in cells show that loss of p62 leads to reduced autophagic flux and decreased production of ubiquitinated protein aggregates in response to misfolded proteins . Knockdown of SQSTM1/p62 in zebrafish produced cerebellar abnormalities and atrophic changes .…”

Section: How Rare Monogenic Diseases Teach Us About Autophagy In Neurmentioning

confidence: 99%

Novel insights into the clinical and molecular spectrum of congenital disorders of autophagy

Teinert

Behne

Wimmer

et al. 2019

J of Inher Metab Disea

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Autophagy is a fundamental and conserved catabolic pathway that mediates the degradation of macromolecules and organelles in lysosomes. Autophagy is particularly important to postmitotic and metabolically active cells such as neurons. The complex architecture of neurons and their long axons pose additional challenges for efficient recycling of cargo. Not surprisingly autophagy is required for normal central nervous system development and function. Several single‐gene disorders of the autophagy pathway have been discovered in recent years giving rise to a novel group of inborn errors of metabolism referred to as congenital disorders of autophagy. While these disorders are heterogeneous, they share several clinical and molecular characteristics including a prominent and progressive involvement of the central nervous system leading to brain malformations, developmental delay, intellectual disability, epilepsy, movement disorders, and cognitive decline. On brain magnetic resonance imaging a predominant involvement of the corpus callosum, the corticospinal tracts and the cerebellum are noted. A storage disease phenotype is present in some diseases, underscoring both clinical and molecular overlaps to lysosomal storage diseases. This review provides an update on the clinical, imaging, and genetic spectrum of congenital disorders of autophagy and highlights the importance of this pathway for neurometabolism and childhood‐onset neurological diseases.

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Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration

Abstract: This study offers an accurate clinical characterization of this recently recognized neurodegenerative disorder caused by biallelic inactivating mutations in and links this phenotype to defective selective autophagy.

Cited by 43 publications

References 41 publications

SQSTM1/p62-Directed Metabolic Reprogramming Is Essential for Normal Neurodifferentiation

SQSTM1/p62-Directed Metabolic Reprogramming Is Essential for Normal Neurodifferentiation

Metabolic regulation of neurodifferentiation in the adult brain

Novel insights into the clinical and molecular spectrum of congenital disorders of autophagy

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