Frontotemporal-TDP and LATE Neurocognitive Disorders: A Pathophysiological and Genetic Approach

Abstract

Frontotemporal lobar degeneration (FTLD) belongs to a heterogeneous group of highly complex neurodegenerative diseases and represents the second cause of presenile dementia in individuals under 65. Frontotemporal-TDP is a subgroup of frontotemporal dementia characterized by the aggregation of abnormal protein deposits, predominantly transactive response DNA-binding protein 43 (TDP-43), in the frontal and temporal brain regions. These deposits lead to progressive degeneration of neurons resulting in cognitive and behavioral impairments. Limbic age-related encephalopathy (LATE) pertains to age-related cognitive decline primarily affecting the limbic system, which is crucial for memory, emotions, and learning. However, distinct, emerging research suggests a potential overlap in pathogenic processes, with some cases of limbic encephalopathy displaying TDP-43 pathology. Genetic factors play a pivotal role in both disorders. Mutations in various genes, such as progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72), have been identified as causative in frontotemporal-TDP. Similarly, specific genetic variants have been associated with an increased risk of developing LATE. Understanding these genetic links provides crucial insights into disease mechanisms and the potential for targeted therapies.

Keywords: frontotemporal lobar degeneration; limbic age-related encephalopathy; progranulin; transactive response DNA-binding protein 43.

Figure 1

Physiological functions of TDP-43. TPD-43 is a nuclear protein with an N-terminal domain (NTD), two RNA recognition motifs (RRM1 and RRM2), and a long C-terminal domain (CTD). TDP-43 regulates the metabolism of nucleic acid by different mechanisms such as pre-miRNA splicing (TDP-43 binds to introns and 3′UTR regions); it binds to mRNA formed and transports it from the nucleus to the cytoplasm through pores. In the cytoplasm, it gives stability to mRNA by binding to 3′UTR region and is believed to regulate the mRNA translation. In addition, TDP-43 has been shown to bind to long non-coding RNAs such as MALAT1 and NEAT1_2 in neurodegenerative diseases; binding is increased in the brain of FTLD/ALS patients. Finally, it helps in the regulation of miRNAs; the primary miRNA (pri-miRNA) is cleaved by Drosha, and the pre-miRNA is formed, which is transported to the cytoplasm by Exportin 5, where it will mature by Dicer, followed by RISC, and result in a functional miRNA of 22 nucleotides. Nuclear export sequence (NES); nuclear localization sequence (NLS); RNA-binding protein (RBP). Created with Biorender.com.

Figure 2

Histopathological subtypes of FTLD-TDP. Type A is characterized mainly by short dystrophic neurites (DNs) and neuronal cytoplasmic inclusions (NCIs) in the superficial neocortical layers. Type B is characterized by NCI in the superficial and deep neocortical layers. Type C is characterized by long DN lesions in the superficial layers. Type D is characterized by lentiform neuronal intranuclear inclusions (NIIs). Glial cytoplasmic inclusion (GCI) presents in white matter only in types A and B. Created with Biorender.com.

Figure 3

Post-translational modifications of TPD-43. The principal post-translational modifications found in TDP-43 protein inclusion associated with pathogenic alterations observed in FTLD/ALS patients are ubiquitination, hyperphosphorylation, and aberrant cleavage. The image shows (a) the ubiquitination of TPD-43 through activation of the ubiquitin–proteasome system (UPS) which affects its protein concentration; (b) TDP-43 being phosphorylated by casein kinase 1 (CK1) which may inhibit the UPS and promotes TDP-43 aggregation; and (c) TDP-43 fragmentation in carboxy-terminal fragments (CTFs). Altogether, these have been proposed to promote TDP-43 aggregation. Created with Biorender.com.

Figure 4

Mechanism of propagation of TDP-43. TDP-43 possesses a long C-terminal domain that is rich in glycine. This region is a prion-like domain where most of the TDP-43 mutations found in ALS occur and the part that promotes aggregation. In humans, TDP-43 is fragmented to TPD-25, and in rats it has been shown to be fragmented to TDP-25 and TDP-35. The proposed spread from one cell to another cell is via exosomes or microvesicles (MVB). Created with Biorender.com.

Figure 5

Progranulin in frontotemporal lobar degeneration. Progranulin contains 7.5 conserved domains, consisting of a repeat of 12 cysteine motifs separated by junction regions where some proteases will be able to cleave progranulin. Progranulin is found mainly in neurons and microglia, where its expression is increased in FTLD; through endocytosis, progranulin is bound to the sortilin receptor and sequestrated in lysosomes which are associated with TMEM106B, which would block its release into extracellular space and reduce its degradation. In adult brains, progranulin is associated with synaptic plasticity; patients with progranulin gene mutation reported an increase in synaptic vesicles and extrasynaptic secretion. Created with Biorender.com.

Figure 6

Alterations due to TDP-43 pathology. TDP-43 pathology induces mutations that trigger important changes in progranulin. In addition, inclusions by TDP-43 can alter brain morphology. Created with Biorender.com.

Figure 7

Alterations in patients with FTLD/ALS. In patients with FTLD/ALS, a reduction in the expression of the C9ORF72 gene is present, and alteration in RBPs as well as in splicing factors and changes in transcription processes are observed. Created with Biorender.com.

Figure 8

Clinical changes in patients with TDP-43. The alteration of the C9ORF72 gene has an impact on important neurological symptoms, the result of NCI and NII lesions, which affect various brain areas. Created with Biorender.com.

Figure 9

ALS-FUS. The opportune detection of ALS-FUS is carried out with immunological tools, where the objective is the detection of inclusions as well as characteristic lesions. Created with Biorender.com.

Figure 10

Changes by clinical phenotypes. Lesions are detected by immunohistochemical tools. Mainly BIBD lesions that occur at specific sites in the brain. Created with Biorender.com.

Figure 11

LATE and FTD. It is common for LATE to occur more often than FTD. It should be noted that a large number of elderly Alzheimer’s patients may be manifesting the pathology due to LATE in some of its stages. Created with Biorender.com.