Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype

Abstract

Frontotemporal Lobar Degeneration (FTLD) is a clinically, pathologically and genetically heterogeneous group of disorders that affect principally the frontal and temporal lobes of the brain. There are three major associated clinical syndromes, behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SD) and progressive non-fluent aphasia (PNFA); three principal histologies, involving tau, TDP-43 and FUS proteins; and mutations in three major genes, MAPT, GRN and C9orf72, along with several other less common gene mutations. All three clinical syndromes can exist separately or in combination with Amyotrophic Lateral Sclerosis (ALS). SD is exclusively a TDP-43 proteinopathy, and PNFA may be so, with both showing tight clinical, histological and genetic inter-relationships. bvFTD is more of a challenge with overlapping histological and genetic features, involvement of any of the three aggregating proteins, and changes in any of the three major genes. However, when ALS is present, all cases show a clear histological phenotype with TDP-43 aggregated proteins, and familial forms are associated with expansions in C9orf72. TDP-43 and FUS are nuclear carrier proteins involved in the regulation of RNA metabolism, whereas tau protein - the product of MAPT - is responsible for the assembly/disassembly of microtubules, which are vital for intracellular transport. Mutations in TDP-43 and FUS genes are linked to clinical ALS rather than FTLD (with or without ALS), suggesting that clinical ALS may be a disorder of RNA metabolism. Conversely, the protein products of GRN and C9orf72, along with those of the other minor genes, appear to form part of the cellular protein degradation machinery. It is possible therefore that FTLD is a reflection of dysfunction within lysosomal/proteasomal systems resulting in failure to remove potentially neurotoxic (TDP-43 and tau) aggregates, which ultimately overwhelm capacity to function. Spread of aggregates along distinct pathways may account for the different clinical phenotypes, and patterns of progression of disease.

CSF SerpinA1 in Creutzfeldt–Jakob disease and frontotemporal lobar degeneration

“…CJD includes six major clinicopathological subtypes that are largely determined by the genotype at the methionine (M)/valine (V) polymorphic codon 129 of the PRNP gene and the type (1 or 2) of disease‐associated prion protein (PrP Sc ) accumulating in the brain . At variance, phenotypic heterogeneity in FTLD spectrum is mainly related to two major proteinopathies, namely FTLD with TDP43 (FTLD‐TDP) and tau pathology (FTLD‐TAU) …”

“…10 At variance, phenotypic heterogeneity in FTLD spectrum is mainly related to two major proteinopathies, namely FTLD with TDP43 (FTLD-TDP) and tau pathology (FTLD-TAU). 11 To further study the role of SerpinA1 in neurodegenerative disorders, we tested CSF SerpinA1 in controls and patients with a definite or probable diagnosis of CJD and FTLD subtypes. To this aim, we took advantage of our previously developed capillary isoelectric focusing (CIEF) immunoassay for the analysis of SerpinA1.…”

New Insight into Alzheimer’s Disease via Caspase 3-cleaved Tau: Pathogenic Role in Tau Oligomer Formation and Memory Deficits

“…Compared to normal tau, genetic mutation in or post-translational modification of tau facilitates the formation of tau aggregates. Similar intracellular protein oligomer and aggregate conformers found in other neurodegenerative diseases, such as mutant Huntingtin in Huntington's disease [9,10], Spinocerebellar ataxia type 1 (SCA) in spinocerebellar ataxia [11], alpha-synuclein in Parkinson's disease [12], and TAR DNAbinding protein-43 (TDP-43) in amyotrophic lateral sclerosis [13] are also thought to induce the respective diseases [14]. Therefore, it is important to study the tau species between oligomers and aggregates found in Alzheimer's disease, with particular attention to their role in memory impairment and the loss of synaptic function.…”

Small-molecule PET Tracers for Imaging Proteinopathies

“…FTLD is a collection of non-AD neurodegenerative disorders affecting primarily the frontal and temporal lobes (157). FTLD can be further divided into three histological subtypes based upon the predominant proteopathy: FTLD-tau, FTLD-TDP, and FTLD-FUS (158). The FTLD-tau subtype includes most primary tauopathies, such as PSP, CBD, and PiD.…”