DCTN1 Binds to TDP-43 and Regulates TDP-43 Aggregation

Deshimaru, Manami; Kinoshita-Kawada, Mariko; Kubota, Kaori; Tanaka, Yasuyoshi; Hirano, Saito; Ishidate, Fumiyoshi; Hiramoto, Masaki; Ishikawa, Mitsuru; Uehara, Yoshio; Hirose, Sachiko; Fujioka, Shinsuke; Iwasaki, Katsunori; Yuasa-Kawada, Junichi; Mishima, Takayasu; Tsuboi, Yoshio

doi:10.3390/ijms22083985

Cited by 24 publications

(18 citation statements)

References 94 publications

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“…Further studies will be needed to determine whether differences in the motility of TDP-43 WT and mutant RNP granules can be explained by loss of direct and/or indirect association with the motor proteins kinesin 1 and dynein ( Chu et al, 2019 ). Recently, it was shown that TDP-43 interacts with dynactin and regulates retrograde transport in a cell line ( Deshimaru et al, 2021 ). Therefore, it will be important to understand whether different ALS-linked mutants and TDP-43 substitutions are able to associate with dynactin and other adaptor proteins.…”

Section: Discussionmentioning

confidence: 99%

Sequence Determinants of TDP-43 Ribonucleoprotein Condensate Formation and Axonal Transport in Neurons

Vishal

Wijegunawardana

Salaikumaran

et al. 2022

Front. Cell Dev. Biol.

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Mutations in TDP-43, a RNA-binding protein with multiple functions in RNA metabolism, cause amyotrophic lateral sclerosis (ALS), but it is uncertain how defects in RNA biology trigger motor neuron degeneration. TDP-43 is a major constituent of ribonucleoprotein (RNP) granules, phase separated biomolecular condensates that regulate RNA splicing, mRNA transport, and translation. ALS-associated TDP-43 mutations, most of which are found in the low complexity domain, promote aberrant liquid to solid phase transitions and impair the dynamic liquid-like properties and motility of RNP transport granules in neurons. Here, we perform a comparative analysis of ALS-linked mutations and TDP-43 variants in order to identify critical structural elements, aromatic and charged residues that are key determinants of TDP-43 RNP transport and condensate formation in neurons. We find that A315T and Q343R disease-linked mutations and substitutions of aromatic residues within the α-helical domain and LARKS, show the most severe defects in TDP-43 RNP granule transport and impair both anterograde and retrograde motility. F313L and F313-6L/Y substitutions of one or both phenylalanine residues in LARKS suggest the aromatic rings are important for TDP-43 RNP transport. Similarly, W334F/L substitutions of the tryptophan residue in the α-helical domain, impair TDP-43 RNP motility (W334L) or anterograde transport (W334F). We also show that R293A and R293K mutations, which disrupt the only RGG in the LCD, profoundly reduce long-range, directed transport and net velocity of TDP-43 RNP granules. In the disordered regions flanking the α-helical domain, we find that F283Y, F397Y or Y374F substitutions of conserved GF/G and SYS motifs, also impair anterograde and/or retrograde motility, possibly by altering hydrophobicity. Similarly, ALS-linked mutations in disordered regions distant from the α-helical domain also show anterograde transport deficits, consistent with previous findings, but these mutations are less severe than A315T and Q343R. Overall our findings demonstrate that the conserved α-helical domain, phenylalanine residues within LARKS and RGG motif are key determinants of TDP-43 RNP transport, suggesting they may mediate efficient recruitment of motors and adaptor proteins. These results offer a possible mechanism underlying ALS-linked TDP-43 defects in axonal transport and homeostasis.

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Section: Discussionmentioning

confidence: 99%

Sequence Determinants of TDP-43 Ribonucleoprotein Condensate Formation and Axonal Transport in Neurons

Vishal

Wijegunawardana

Salaikumaran

et al. 2022

Front. Cell Dev. Biol.

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“…Particularly, the latter shows some clinical and pathological similarities with those related to the DNAJB2 phenotype. It is characterized clinically by early‐onset parkinsonism, depression/apathy and central hypoventilation, and pathologically by degeneration of dopaminergic neurons and TDP‐43 proteinopathy [18].…”

Section: Discussionmentioning

confidence: 99%

DNAJB2‐related Charcot‐Marie‐Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening

Saveri

Magri

Maderna

et al. 2022

Euro J of Neurology

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Background and purpose Mutations in DNAJB2 are associated with autosomal recessive hereditary motor neuropathies/ Charcot‐Marie‐Tooth disease type 2 (CMT2). We describe an Italian family with CMT2 due to a homozygous DNAJB2 mutation and provide insight into the pathomechanisms. Methods Patients with DNAJB2 mutations were characterized clinically, electrophysiologically and by means of skin biopsy. mRNA and protein levels were studied in lymphoblastoid cells (LCLs) from patients and controls. Results Three affected siblings were found to carry a homozygous DNAJB2 null mutation segregating with the disease. The disease manifested in the second to third decade of life. Clinical examination showed severe weakness of the thigh muscles and complete loss of movement in the foot and leg muscles. Sensation was reduced in the lower limbs. All patients had severe hearing loss and the proband also had Parkinson’s disease (PD). Nerve conduction studies showed an axonal motor and sensory length‐dependent polyneuropathy. DNAJB2 expression studies revealed reduced mRNA levels and the absence of the protein in the homozygous subject in both LCLs and skin biopsy. Interestingly, we detected phospho‐alpha‐synuclein deposits in the proband, as already seen in PD patients, and demonstrated TDP‐43 accumulation in patients’ skin. Conclusions Our results broaden the clinical spectrum of DNAJB2‐related neuropathies and provide evidence that DNAJB2 mutations should be taken into account as another causative gene of CMT2 with hearing loss and parkinsonism. The mutation likely acts through a loss‐of‐function mechanism, leading to toxic protein aggregation such as TDP‐43. The associated parkinsonism resembles the classic PD form with the addition of abnormal accumulation of phospho‐alpha‐synuclein.

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“…Such mutation produces a G59S substitution in DCTN1 CAP-Gly domain that alters the folding of DCTN1 microtubule-binding domain, reducing the affinity of the mutant protein for microtubules. G59S DCTN1 tends to misfold and form neurotoxic aggregates that were shown to sequester dynein, mitochondria, and TDP-43 (Puls et al 2003 , 2005 ; Levy et al 2006 ; Deshimaru et al 2021 ). Additional DCTN1 mutations lying both in DCTN1 CAP-Gly domain and in its dynein-binding domain have then been identified in ALS (Münch et al 2004 ; Stockmann et al 2013 ; Liu et al 2014 , 2017 ), including those forms with an FTD component (Münch et al 2005 ).…”

Section: Autophagic Genes Involved In Alsmentioning

confidence: 99%

Autophagy Dysfunction in ALS: from Transport to Protein Degradation

Cozzi

Ferrari

2022

J Mol Neurosci

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting upper and lower motor neurons (MNs). Since the identification of the first ALS mutation in 1993, more than 40 genes have been associated with the disorder. The most frequent genetic causes of ALS are represented by mutated genes whose products challenge proteostasis, becoming unable to properly fold and consequently aggregating into inclusions that impose proteotoxic stress on affected cells. In this context, increasing evidence supports the central role played by autophagy dysfunctions in the pathogenesis of ALS. Indeed, in early stages of disease, high levels of proteins involved in autophagy are present in ALS MNs; but at the same time, with neurodegeneration progression, autophagy-mediated degradation decreases, often as a result of the accumulation of toxic protein aggregates in affected cells. Autophagy is a complex multistep pathway that has a central role in maintaining cellular homeostasis. Several proteins are involved in its tight regulation, and importantly a relevant fraction of ALS-related genes encodes products that directly take part in autophagy, further underlining the relevance of this key protein degradation system in disease onset and progression. In this review, we report the most relevant findings concerning ALS genes whose products are involved in the several steps of the autophagic pathway, from phagophore formation to autophagosome maturation and transport and finally to substrate degradation.

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DCTN1 Binds to TDP-43 and Regulates TDP-43 Aggregation

Cited by 24 publications

References 94 publications

Sequence Determinants of TDP-43 Ribonucleoprotein Condensate Formation and Axonal Transport in Neurons

Sequence Determinants of TDP-43 Ribonucleoprotein Condensate Formation and Axonal Transport in Neurons

DNAJB2‐related Charcot‐Marie‐Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening

Autophagy Dysfunction in ALS: from Transport to Protein Degradation

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