Fine structural analysis of the neuronal inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy

Abstract

TAR DNA-binding protein of 43 kDa (TDP-43) is a major component of the pathological inclusions of frontotemporal lobar degeneration with TDP-43 proteinopathy, also called FTLD with ubiquitinpositive, tau-negative inclusions (FTLD-U), and motor neuron disease (MND). TDP-43 is predominantly expressed in the nucleus and regulates gene expression and splicing. In FTLD with TDP-43 proteinopathy, neuronal inclusions present variably as cytoplasmic inclusions (NCIs), dystrophic neurites (DNs), and intranuclear inclusions (NIIs), leading to a fourfold neuropathological classification correlating with genotype. There have been few fine structural studies of these inclusions. Thus, we undertook an immunoelectron microscopic study of FTLD with TDP-43 proteinopathy, including sporadic and familial cases with progranulin (GRN) mutation. TDP-43-immunoreactive inclusions comprised two components: granular and filamentous. Filament widths, expressed as mean (range) were: NCI, 9 nm (4-16 nm); DN, 10 nm (5-16 nm); NII, 18 nm (9-50 nm). Morphologically distinct inclusion components may reflect the process of TDP-43 aggregation and interaction with other proteins: determining these latter may contribute towards understanding the heterogeneous pathogenesis of FTLD with TDP-43 proteinopathy.

TDP-43 localizes in mRNA transcription and processing sites in mammalian neurons

“…Within the euchromatin domains (Thorpe et al, 2008;present results), TDP-43 is specifically concentrated in PFs, nuclear structures enriched in nascent pre-mRNA transcripts and splicing factors (Spector et al, 1983;Fakan 1994;Spector, 2001;Biggiogera et al, 2008), and also related to the biogenesis of intron-derived miRNAs (Lin et al, 2006). This nuclear localization has special functional relevance because transcription and cotranscriptional splicing of pre-mRNAs have been shown to occur in PFs (Fakan, 1994;Cmarko et al, 1999;Spector et al, 1983).…”

“…Thus, TDP-43 is the major disease protein for frontotemporal lobar degeneration (FTLD), the second most common cause of dementia after Alzheimer's disease, and amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder (Neumann et al, 2006). In both diseases, TDP-43 is depleted from the nucleus and accumulates in ubiquitin-positive cytoplasmic aggregates of affected neurons (Arai et al, 2006;Davison et al, 2007;Thorpe et al, 2008;Woulfe, 2008). However, whether the pathogenic role of the cytoplasmic TDP-43 aggregates is due to loss of the nuclear functions of the TDP-43 or gain of toxic function in the cytoplasm is subject to a lively debate .…”

“…It has two RNA recognition motifs (RRM1 and RRM2) flanked by an N-terminal and C-terminal tail (Wang et al, 2004;Ayala et al, 2008;Buratti and Baralle, 2008). Under physiological conditions, TDP-43 is ubiquitously distributed in neuronal and non-neuronal cells and has a predominant nuclear localization, although low levels of this protein are present in the cytoplasm (Ayala et al, 2008;Winton et al, 2008;Turner et al, 2008;Buratti and Baralle, 2008;Thorpe et al, 2008). TDP-43 is a multifunctional protein involved in several aspects of RNA metabolism such as the regulation of transcription, alternative splicing and mRNA stability (Strong et al, 2007;Buratti and Baralle, 2008;Ayala et al, 2008).…”

Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases

“…This list includes β-amyloid (Aβ) in senile plaques and tau in neurofibrillary tangles (NFTs) of Alzheimer’s disease 1,2 , α-synuclein (α-syn) in Lewy bodies and Lewy neurites of Parkinson’s disease 3 , TDP-43 aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration 4 , polyglutamine (polyQ)-rich huntingtin inclusions in Huntington’s disease 5 and prion plaques in Creutzfeldt-Jakob disease (CJD) 6 . When viewed by electron microscopy, most of these protein aggregates consist of 8- to 20-nm wide filaments and are characterized by enriched β-pleated sheet structures (‘amyloid’) that can be stained by dyes such as Congo Red or thioflavin S (ThS) 7,8 , with the exception of TDP-43 inclusions, in which the aggregates comprise mostly granular non-amyloid fibrils 9,10 .…”

Role of the ubiquitin–proteasome system in nervous system function and disease: using C. elegans as a dissecting tool

“…The accumulation of misfolded protein aggregates is observed in a range of neurological diseases, which includes PD, AD, amyotrophic lateral sclerosis, frontotemporal dementia, and polyglutamine (polyQ) expansion disorders, among others [174][175][176][177][178][179]. These aggregates are often immunoreactive for components of the UPS, namely ubiquitin [180][181][182].…”