Dynactin Deficiency in the CNS of Humans with Sporadic ALS and Mice with Genetically Determined Motor Neuron Degeneration

Kuźma‐Kozakiewicz, Magdalena; Chudy, Agnieszka; Kaźmierczak, Beata; Dziewulska, Dorota; Usarek, Ewa; Barańczyk‐Kuźma, Anna

doi:10.1007/s11064-013-1160-7

Cited by 33 publications

(25 citation statements)

References 49 publications

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“…The changes in dynactin DCTN1 expression in PBMCs of SALS patients were the opposite to those observed earlier in the brain cortex and the spinal cord [38]. In SALS brain motor cortex the expression of DCTN1 and DCTN3 mRNA was higher than in the sensory cortex.…”

Section: Discussioncontrasting

confidence: 62%

“…Many papers indicated that disorders in the intracellular transport might be crucial for the initiation or progression of motor neuron degeneration [35,41,42,43,44]. In our previous studies, we observed important changes in the expression of tau isoforms, kinesins and dynactin in various regions of the CNS obtained from autopsies of SALS patients and transgenic mice with symptoms of motor neuron degeneration [36,37,38,45]. In the present work we investigated the expression of motor proteins in PBMCs obtained from a cohort of Polish SALS patients in comparison with healthy blood donors, and patients with other neurological diseases such as atypical parkinsonism and ALS-mimicking disorders.…”

Section: Discussionmentioning

confidence: 94%

“…Restricted access to human nervous tissue has promoted the use of transgenic animal disease models. Although very useful, they do not always reflect the clinical and pathological changes present in human subjects [37,38,40]. Many papers indicated that disorders in the intracellular transport might be crucial for the initiation or progression of motor neuron degeneration [35,41,42,43,44].…”

Section: Discussionmentioning

confidence: 99%

“…Kinesin and dynactin subunit expression on the mRNA level was studied by real-time quantitative PCR (qPCR), as indicated earlier [37,38]. Total RNA was extracted from PBMCs by a QIAamp RNA Blood Mini Kit (Qiagen, USA) according to the manufacturer's standard instructions.…”

Section: Methodsmentioning

confidence: 99%

“…In our earlier studies we showed several changes in the expression of crucial components of axonal transport in the CNS of humans with SALS and transgenic mice with SOD1-related ALS (familial ALS) [36,37,38]. In the present work we focused on the expression of motor proteins involved in the anterograde (KIF1B, KIF5C) and the retrograde (KIFC3, dynactin) transport in peripheral blood mononuclear cells (PBMCs) obtained from SALS patients, healthy control subjects and patients with other neurological diseases (disease control).…”

Section: Introductionmentioning

confidence: 99%

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Alteration of Motor Protein Expression Involved in Bidirectional Transport in Peripheral Blood Mononuclear Cells of Patients with Amyotrophic Lateral Sclerosis

Kuźma‐Kozakiewicz

Kaźmierczak²,

Chudy³

et al. 2016

Neurodegener Dis

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Background: Sporadic amyotrophic lateral sclerosis (SALS) is a fatal motor neuron degenerative disease of unclear pathogenesis. Disturbances of intracellular transport are possible causes of the disease. Objective: We evaluated the expression of motor proteins involved in the anterograde (kinesins KIF1B, KIF5C) and retrograde (KIFC3, dynactin subunits DCTN1 and DCTN3) intracellular transport in peripheral blood mononuclear cells (PBMCs). Materials and Methods: PBMCs were obtained from 74 SALS patients with different clinical phenotypes, 65 blood donors (healthy control I), and 29 cases with other neurological diseases (disease control II) divided into subgroups IIA (atypical parkinsonism) and IIB (ALS-mimicking disorders). mRNA expression was studied by real-time qPCR, and protein level by Western blotting. Results: In SALS, KIF5C and KIFC3 expression was significantly lower and DCTN1 higher than in control I, and dependent of age. KIF1B expression was significantly higher in SALS than in subgroup IIB, whereas DCTN1 and DCTN3 were higher in SALS than in subgroup IIA. All changes in the studied proteins were statistically significant in classic ALS but not in progressive muscular atrophy. Conclusion: In SALS, and especially in classic ALS, the changes in motor protein expression may alter bidirectional intracellular transport in PBMCs. More studies are needed to find out whether the levels of KIF5C and DCTN1 may be useful in ALS diagnosis, and whether KIF1B expression may discriminate ALS from ALS-mimicking disorders.

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Section: Discussioncontrasting

confidence: 62%

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Alteration of Motor Protein Expression Involved in Bidirectional Transport in Peripheral Blood Mononuclear Cells of Patients with Amyotrophic Lateral Sclerosis

Kuźma‐Kozakiewicz

Kaźmierczak²,

Chudy³

et al. 2016

Neurodegener Dis

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New phenotype of DCTN1‐related spectrum: early‐onset dHMN plus congenital foot deformity

Tian

Liu

Zhou

et al. 2020

Ann Clin Transl Neurol

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Objective To describe the clinical and genetic features of two patients with different phenotypes due to various Dynactin 1 (DCTN1) gene mutations and further explore the phenotype–genotype relationship. Methods Patient 1 is a 23‐year‐old man with congenital foot deformity and life‐long distal muscle weakness and atrophy. Patient 2 is a 48‐year‐old woman with adult‐onset progressive weakness, lower limbs atrophy, and pyramid bundle signs. Electrophysiology test showed normal nerve conduction velocity of both patients and neurogenic changes in needle electromyography. Open sural nerve biopsy for Patient 1 showed slight loss of myelinated nerve fibers. Both patients were performed with whole‐exome sequencing followed by functional study of identified variants. Results Two mutations in DCTN1 gene were identified in Patient 1 (c.626dupC) and Patient 2 (c.3823C>T), respectively. In vitro, the wild type mostly located in cytoplasm and colocalized with α‐tubulin. However, c.626dupC tended to be trapped into nuclear and the c.3823C>T formed cytoplasmic aggregates, both losing colocalization with α‐tubulin. Western blotting showed a truncated mutant with less molecular weight of c.626dupC was expressed. Interpretation We identify two novel DCTN1 mutations causing different phenotypes: (1) early‐onset distal hereditary motor neuropathy plus congenital foot malformation and (2) amyotrophic lateral sclerosis, respectively. We provide the initial evidence that foot developmental deficiency probably arises from subcellular localizing abnormality of Dynactin 1, revealing DCTN1‐related spectrum is still expanding.

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Transcriptomic analysis of frontotemporal lobar degeneration with TDP-43 pathology reveals cellular alterations across multiple brain regions

et al. 2021

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Frontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative disorders affecting the frontal and temporal lobes of the brain. Nuclear loss and cytoplasmic aggregation of the RNA-binding protein TDP-43 represents the major FTLD pathology, known as FTLD-TDP. To date, there is no effective treatment for FTLD-TDP due to an incomplete understanding of the molecular mechanisms underlying disease development. Here we compared post-mortem tissue RNA-seq transcriptomes from the frontal cortex, temporal cortex and cerebellum between 28 controls and 30 FTLD-TDP patients to profile changes in cell-type composition, gene expression and transcript usage. We observed downregulation of neuronal markers in all three regions of the brain, accompanied by upregulation of microglia, astrocytes, and oligodendrocytes, as well as endothelial cells and pericytes, suggesting shifts in both immune activation and within the vasculature. We validate our estimates of neuronal loss using neuropathological atrophy scores and show that neuronal loss in the cortex can be mainly attributed to excitatory neurons, and that increases in microglial and endothelial cell expression are highly correlated with neuronal loss. All our analyses identified a strong involvement of the cerebellum in the neurodegenerative process of FTLD-TDP. Altogether, our data provides a detailed landscape of gene expression alterations to help unravel relevant disease mechanisms in FTLD.

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Dynactin Deficiency in the CNS of Humans with Sporadic ALS and Mice with Genetically Determined Motor Neuron Degeneration

Cited by 33 publications

References 49 publications

Alteration of Motor Protein Expression Involved in Bidirectional Transport in Peripheral Blood Mononuclear Cells of Patients with Amyotrophic Lateral Sclerosis

Alteration of Motor Protein Expression Involved in Bidirectional Transport in Peripheral Blood Mononuclear Cells of Patients with Amyotrophic Lateral Sclerosis

New phenotype of DCTN1‐related spectrum: early‐onset dHMN plus congenital foot deformity

Transcriptomic analysis of frontotemporal lobar degeneration with TDP-43 pathology reveals cellular alterations across multiple brain regions

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