Spinocerebellar ataxia type 2 (SCA2) is associated with TDP-43 pathology

Toyoshima, Yasuko; Tanaka, Hajime; Shimohata, Mitsuteru; Kimura, Kakuhei; Morita, Takashi; Kakita, Akiyoshi; Takahashi, Hitoshi

doi:10.1007/s00401-011-0862-7

Cited by 40 publications

(39 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Once TDP-43 was discovered to be a key component in ALS, TDP-43-ir NCIs were detected in neurons from various areas of SCA2 disease brain [4, 40] and in lower motor neurons and axons in patients with Machado-Joseph disease (also known as SCA3) [35, 38]. Interestingly, in the reported cases, co-localization of TDP-43 and mutant polyglutamine proteins has never been observed, and coexistence of these proteins in the same neurons is not frequent [38, 40]. Thus, the features appear to be similar to those of our two cases.…”

Section: Discussionmentioning

confidence: 99%

Coexistence of Huntington’s disease and amyotrophic lateral sclerosis: a clinicopathologic study

et al. 2012

Self Cite

View full text Add to dashboard Cite

We report a retrospective case series of four patients with genetically confirmed Huntington’s disease (HD) and sporadic amyotrophic lateral sclerosis (ALS), examining the brain and spinal cord in two cases. Neuropathological assessment included a polyglutamine recruitment method to detect sites of active polyglutamine aggregation, and biochemical and immunohistochemical assessment of TDP-43 pathology. The clinical sequence of HD and ALS varied, with the onset of ALS occurring after the mid-fifties in all cases. Neuropathologic features of HD and ALS coexisted in both cases examined pathologically: neuronal loss and gliosis in the neostriatum and upper and lower motor neurons, with Bunina bodies and ubiquitin-immunoreactive skein-like inclusions in remaining lower motor neurons. One case showed relatively early HD pathology while the other was advanced. Expanded polyglutamine-immunoreactive inclusions and TDP-43-immunoreactive inclusions were widespread in many regions of the CNS, including the motor cortex and spinal anterior horn. Although these two different inclusions coexist in a small number of neurons, the two proteins did not co-localize within inclusions. The regional distribution of TDP-43-immunoreactive inclusions in the cerebral cortex was somewhat similar to that of expanded polyglutamine-immunoreactive inclusions. In the one case examined by TDP-43 immunoblotting, similar TDP-43 isoforms were observed as in ALS. Our findings suggest the possibility that a rare subset of older HD patients is prone to develop features of ALS with an atypical TDP-43 distribution that resembles that of aggregated mutant huntingtin. Age-dependent neuronal dysfunction induced by mutant polyglutamine protein expression may contribute to later-life development of TDP-43 associated motor neuron disease in a small subset of patients with HD.

show abstract

Section: Discussionmentioning

confidence: 99%

Coexistence of Huntington’s disease and amyotrophic lateral sclerosis: a clinicopathologic study

et al. 2012

Self Cite

View full text Add to dashboard Cite

show abstract

“…5). Furthermore, SCA2 exhibits TDP-43-positive protein aggregates, which do not overlap with 1C2 stained material [172].…”

Section: Sca2mentioning

confidence: 93%

Brain pathology of spinocerebellar ataxias

et al. 2012

View full text Add to dashboard Cite

The autosomal dominant cerebellar ataxias (ADCAs) represent a heterogeneous group of neurodegenerative diseases with progressive ataxia and cerebellar degeneration. The current classification of this disease group is based on the underlying genetic defects and their typical disease courses. According to this categorization, ADCAs are divided into the spinocerebellar ataxias (SCAs) with a progressive disease course, and the episodic ataxias (EA) with episodic occurrences of ataxia. The prominent disease symptoms of the currently known and genetically defined 31 SCA types result from damage to the cerebellum and interconnected brain grays and are often accompanied by more specific extra-cerebellar symptoms. In the present review, we report the genetic and clinical background of the known SCAs and present the state of neuropathological investigations of brain tissue from SCA patients in the final disease stages. Recent findings show that the brain is commonly seriously affected in the polyglutamine SCAs (i.e. SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) and that the patterns of brain damage in these diseases overlap considerably in patients suffering from advanced disease stages. In the more rarely occurring non-polyglutamine SCAs, post-mortem neuropathological data currently are scanty and investigations have been primarily performed in vivo by means of MRI brain imaging. Only a minority of SCAs exhibit symptoms and degenerative patterns allowing for a clear and unambiguous diagnosis of the disease, e.g. retinal degeneration in SCA7, tau aggregation in SCA11, dentate calcification in SCA20, protein depositions in the Purkinje cell layer in SCA31, azoospermia in SCA32, and neurocutaneous phenotype in SCA34. The disease proteins of polyglutamine ataxias and some non-polyglutamine ataxias aggregate as cytoplasmic or intranuclear inclusions and serve as morphological markers. Although inclusions may impair axonal transport, bind transcription factors, and block protein quality control, detailed molecular and pathogenetic consequences remain to be determined.

show abstract

“…The shared pathology includes neuronal cytoplasmic inclusions (NCIs), loss of the normal nuclear TDP-43, ubiquitination and hyperphosphorylation of TDP-43 and lastly formation of abnormal fragments of TDP-43 in post-mortem tissue Nonaka et al 2009;Zhang et al 2009). However, TDP-43 is also found in inclusions in Machado-Joseph disease (Tan et al 2009), spinocerebellar ataxia (Toyoshima et al 2011), Huntington's disease (Schwab et al 2008), Alzheimer's disease (Davidson et al 2011), inclusion body myositis (Weihl et al 2008) and Parkinson's disease (NakashimaYasuda et al 2007), suggesting that TDP-43 accumulation is not ALS or FTD specific. Of interest, AD-associated Aβ has been implicated in triggering the phosphorylation and cytosolic accumulation of pathogenic TDP-43 in rodent models and in brain autopsies from AD patients (Herman et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Addition of exogenous SOD1 aggregates causes TDP-43 mislocalisation and aggregation

Zeineddine

Farrawell

Lambert-Smith

et al. 2017

Cell Stress and Chaperones

View full text Add to dashboard Cite

ALS is characterised by a focal onset of motor neuron loss, followed by contiguous outward spreading of pathology throughout the nervous system, resulting in paralysis and death generally within a few years after diagnosis. The aberrant release and uptake of toxic proteins including SOD1 and TDP-43 and their subsequent propagation, accumulation and deposition in motor neurons may explain such a pattern of pathology. Previous work has suggested that the internalization of aggregates triggers stress granule formation. Given the close association of stress granules and TDP-43, we wondered whether internalisation of SOD1 aggregates stimulated TDP-43 cytosolic aggregate structures. Addition of recombinant mutant G93A SOD1 aggregates to NSC-34 cells was found to trigger a rapid shift of TDP-43 to the cytoplasm where it was still accumulated after 48 h. In addition, SOD1 aggregates also triggered cleavage of TDP-43 into fragments including a 25 kDa fragment. Collectively, this study suggests a role for protein aggregate uptake in TDP-43 pathology.

show abstract

Spinocerebellar ataxia type 2 (SCA2) is associated with TDP-43 pathology

Cited by 40 publications

References 6 publications

Coexistence of Huntington’s disease and amyotrophic lateral sclerosis: a clinicopathologic study

Coexistence of Huntington’s disease and amyotrophic lateral sclerosis: a clinicopathologic study

Brain pathology of spinocerebellar ataxias

Addition of exogenous SOD1 aggregates causes TDP-43 mislocalisation and aggregation

Contact Info

Product

Resources

About