Review: Molecular pathology of frontotemporal lobar degenerations

Abstract

Frontotemporal lobar degeneration (FTLD) is a group of disorders that principally affect the frontal and temporal lobes of the brain. In many parts of the world, FTLD is rapidly becoming a serious health burden on society and, as a result, the molecular mechanisms that underlie its onset and development have been the target of intense research efforts in recent years. Nonetheless, despite crucial pathological and genetic discoveries in this area much is still uncertain about how the many genes associated with this disease cause the observed neurodegeneration. Moreover, it has not been easy to define the molecular mechanisms that account for the clinical and pathological heterogeneity of the various FTLD subtypes, characterized by aggregates of Tau, TAR‐DNA‐Binding Protein‐43 (TDP‐43), and less often Fused in Sarcoma (FUS) protein. In this review, we will examine some of the emerging discoveries in this field: from the recent importance of autoimmunity to the presence of substantial variations in the composition and localization of TDP‐43 and FUS brain aggregates in patients, and how they might affect the course of the disease. All together, these new results demonstrate how the observed clinical heterogeneity underlies considerable complexity at both the molecular and the disease pathway level. A better characterization of all this complexity will be essential for a more accurate stratification of patient cohorts for further studies and, eventually, for trials of therapy.

Partial Failure of Proteostasis Systems Counteracting TDP-43 Aggregates in Neurodegenerative Diseases

“…Several studies have shown abnormalities of Ca 2+ homeostasis in both FTLD and ALS [7,8,37,38]. By using confocal microscopy and Fluo4 as a specific fluorescent probe, we found that transfected TDP-43 aggregates triggered a significant and extensive increase of Ca 2+ levels in the cytosol of N2A neuroblastoma cells (Figure 2).…”

“…A number of physiological functions are perturbed in FTLD and ALS, including impaired protein homeostasis, RNA dysmetabolism, and reduced nucleocytoplasmic transport of mRNAs and proteins [4,7,8]. The cytoplasmic deposition of TDP-43 occurs concomitantly with the depletion of native TDP-43 from the nucleus [1], causing neurodegeneration in both FTLD-U and ALS by a combination of gain-of-function (GOF) and loss-of-function (LOF) mechanisms [1,9,10].…”

An update on human astrocytes and their role in development and disease

“…FTLD is the second most common cause of presenile dementia and it is a heterogeneous group of disorders that targets the temporal and frontal lobes of the brain (Borroni, Alberici, & Buratti, 2019). FTLD has been associated with ALS so much that they are considered part of the same disease spectrum: 15% of FTLD cases develop motor symptoms and up to 50% of ALS cases present cognitive impairment, although only 20% are effectively diagnosed with FTLD (Lomen-Hoerth, Anderson, & Miller, 2002;Taylor et al, 2016).…”

Gait Ignition Failure in JNPL3 Human Tau-mutant Mice

“…Cognitive deficits and motor dysfunction are frequently observed behavioral phenotypes in genetic animal models of neurodegenerative diseases [1]. Neurofibrillary tangles (NFT) composed of highly phosphorylated forms of microtubule-associated protein tau are commonly found in various tauopathies such as Alzheimer's disease (AD) [2], Pick's disease [3], progressive supranuclear palsy [4], frontotemporal dementia [5], Parkinsonism linked to chromosome 17 (FTDP-17) [6], and corticobasal degeneration [47], implicating tau dysfunction in the pathology underpinning neurodegeneration and behavioral deficits. Preceding the onset of neurodegeneration, hyperphosphorylated tau proteins undergo abnormal assembly, leading to the formation of diverse tau protein species [8].…”