The most recent discovery of a pathological hexanucleotide repeat expansion in the gene C9orf72 as a frequent cause of both FTLD and ALS has eventually confirmed the association of these two at first sight distinct neurodegenerative diseases.
Distinct TDP-43 inclusion morphologies in the anterior cingulate cortex of FTLD and FTLD-ALS may be linked to heterogeneity in the ubiquitination of pathological TDP-43 inclusions, with the present study providing evidence to suggest the involvement of distinct pathomechanisms in these two overlapping clinical syndromes.
Here, we review the current status of research pursued to identify specific indicators to predict or exclude TDP-43 pathology in the ALS-FTLD spectrum disorders and findings on candidates for prognosis and monitoring of disease progression in TDP-43 proteinopathies with a focus on TDP-43 with its pathological forms, neurochemical and imaging biomarkers.
The identification of pathologic TDP-43 aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, followed by the discovery of dominantly inherited point mutations in TDP-43 in familial ALS, have been critical insights into the mechanism of these untreatable neurodegenerative diseases.
In line with a potential pathological overlap of FTLD and NCL, Ctsd(-/-) mice, a model for NCL, show elevated levels of the FTLD-associated proteins GRN and TMEM106B.
Haploinsufficiency caused by autosomal dominant mutations within the GRN gene leads to frontotemporal lobar degeneration, a progressive neuronal atrophy that presents in patients as frontotemporal dementia.
In this article, we will review the contemporary clinical, genetic and neuropathological characteristics of the frontotemporal syndromes of ALS and propose that as opposed to being a FTLD in which TDP-43 is the primary disease protein (FTLD-TDP) and that the frontotemporal syndromes of ALS represent a hybrid of both TDP-43 and tau pathology.
This case confirms progranulin plasma levels as a reliable biomarker to identify GRN deletion carriers and discriminate between FTLD and other dementias which may mimic it.
Phenotypic variability associated with the C9ORF72 hexanucleotide repeat expansion: a sporadic case of frontotemporal lobar degeneration with prodromal hyposmia and predominant semantic deficits.
Understanding the basis of the proposed mechanisms and shared pathways, as well as interactions with known key proteins such as TAR DNA-binding protein (TDP-43) are needed to clarify the pathology of ALS and/or FTLD, and make possible steps toward therapy development.
Mutations in the progranulin gene (PGRN) are a major cause of frontotemporal lobar degeneration with tau-negative and ubiquitin-positive neuronal inclusions.
To achieve this, we systematically screened ALS/FTLD-associated and synthetic TDP-43 isoforms via same-site gene insertion and neural expression in Drosophila; followed by transposon-based motor neuron-specific transgenesis in a chick vertebrate system.
Tar DNA binding protein 43 (TDP-43) is the major component of pathological deposits in frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and in amyotrophic lateral sclerosis (ALS).
Transactive response DNA-binding protein 43kD (TDP-43) is a major component of tau-negative and ubiquitin-positive inclusions that characterize ALS (amyotrophic lateral sclerosis) and FTLD (frontotemporal lobar degeneration).
More recently, progranulin gene mutations were recognized in association with the familial form of FTLD and a hexanucleotide repetition in C9ORF72 has been shown to be responsible for familial FTLD and amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are characterized by cytoplasmic protein aggregates in the brain and spinal cord that include TAR-DNA binding protein 43 (TDP-43).
Our results indicate that the serum PGRN level is a reliable biomarker for diagnosing and early detection of frontotemporal lobar degeneration caused by PGRN null mutations, and provided the first in vivo evidence that at least some missense mutations in PGRN may lead to a (partial) loss of PGRN.
Taken together, inhibition of nuclear import of TDP-43 by cytoplasmic poly-GA inclusions causally links the two main aggregating proteins in C9orf72 ALS/FTLD pathogenesis.
Mutations in one of these genes (GRN), which encodes progranulin, have been implicated in up to a quarter of cases of frontotemporal lobar degeneration with TDP-43 (TAR DNA-binding protein 43)-positive inclusions; currently, there are more than 60 known pathogenic mutations of the gene.
A repeat expansion in the C9orf72 gene has recently been identified as a major cause of familial and sporadic frontotemporal lobar degeneration and amyotrophic lateral sclerosis.