RNA Binding Proteins and the Pathogenesis of Frontotemporal Lobar Degeneration

Abstract

Frontotemporal dementia is a group of early onset dementia syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology that can be classified based on the formation of abnormal protein aggregates involving tau and two RNA binding proteins, TDP-43 and FUS. Although elucidation of the mechanisms leading to FTLD pathology is in progress, recent advances in genetics and neuropathology indicate that a majority of FTLD cases with proteinopathy involving RNA binding proteins show highly congruent genotype-phenotype correlations. Specifically, recent studies have uncovered the unique properties of the low-complexity domains in RNA binding proteins that can facilitate liquid-liquid phase separation in the formation of membraneless organelles. Furthermore, there is compelling evidence that mutations in FTLD genes lead to dysfunction in diverse cellular pathways that converge on the endolysosomal pathway, autophagy, and neuroinflammation. Together, these results provide key mechanistic insights into the pathogenesis and potential therapeutic targets of FTLD.

Keywords: ALS; FTD; FTLD; FUS; RNA binding proteins; TDP-43; amyotrophic lateral sclerosis; frontotemporal dementia; frontotemporal lobar degeneration; hydrogels; liquid droplets; low-complexity domain.

Figure 1

Summary of the clinical syndromes, neuropathology, and genetics of FTD. The six clinical syndromes include bvFTD, svPPA, nfvPPA, FTD-MND, CBS, and PSP-RS. A small number of patients with bvFTD, svPPA, nfvPPA, or CBS have Alzheimer’s disease as the underlying pathology. Based on the proteinopathy involved, the neuropathology of FTLD can be classified as FTLD-tau, FTLD-TDP, or FTLD-FUS. Genetic mutations associated with each molecular subtype are italicized. A rare subtype of FTLD (FTLD-3) has been reported in patients with mutations in the CHMP2B gene. The designations 3R and 4R indicate, respectively, three microtubule binding repeats and four tau repeats. Abbreviations: aFTLD-U, atypical FTLD-ubiquitin; AGD, argyrophilic grain disease; BIBD, basophilic inclusion body disease; bvFTD, behavioral variant FTD; CBD, corticobasal degeneration; CBS, corticobasal syndrome; CTE, chronic traumatic encephalopathy; FTD, frontotemporal dementia; FTD-MND, FTD with motor neuron disease; FTDP-17, familial FTD with mutations on the MAPT gene on chromosome 17; FTLD, frontotemporal lobar degeneration; GGT, globular glial tauopathy; MST, multisystem tauopathy; nfvPPA, nonfluent/agrammatic variant primary progressive aphasia; NIFID/NIBD, neuronal intermediate filament inclusion disease/neurofilament inclusion body disease; NOS, not otherwise specified; PSP-RS, progressive supranuclear palsy–Richardson syndrome; svPPA, semantic variant primary progressive aphasia.

Figure 2

Neuropathology of FTLD. Subtypes of (a–c) FTLD-tau and (d–f) FTLD-TDP are distinguished by the morphology and distribution of their characteristic lesions. (a) Pick bodies in Pick’s disease; (b) a tufted astrocyte in PSP; (c) an astrocytic plaque in CBD; (d) small compact or crescentic neuronal cytoplasmic inclusions and short, thin neuropil threads in FTLD-TDP type A; (e) diffuse granular or speckled neuronal cytoplasmic inclusions, with a relative paucity of neuropil threads, in FTLD-TDP type B; and (f) long, tortuous dystrophic neurites in FTLD-TDP type C. TDP-43 can be seen within the nucleus in neurons lacking inclusions, but it mislocalizes to the cytoplasm within inclusion-bearing neurons. (g) Immunohistochemical stain for FUS highlights the prominent FUS-positive staining in basophilic inclusions in the cytoplasm of spinal motor neurons in an ALS-FUS case. (h,i) Ultrastructural analyses of the same case as shown in panel g show that these inclusions (h) contain filamentous aggregates measuring 15–20 nm in diameter and (i) are immunoreactive for FUS antibody. (j) The most common subtype of FTLD-FUS is aFTLD-U, characterized by signature FUS immunoreactive vermiform intranuclear inclusions. Immunostains were performed using antibodies to (a) 3R tau, (b,c) phospho-tau (CP-13), (d–f) TDP-43, and (g,i,j) FUS. The scale bar in panel f is applicable to panels a–e. Abbreviations: aFTLD-U, atypical FTLD-ubiquitin; ALS, amyotrophic lateral sclerosis; CBD, corticobasal degeneration; FTLD, frontotemporal lobar degeneration; EM, electron microscopy; IHC, immunohistochemistry; ImmEM, immunogold electron microscopy; PSP, progressive supranuclear palsy.

Figure 3

Liquid–liquid phase separation (LLPS) governs the formation of membraneless organelles. (a) Schematic representing the low-complexity (LC) domain, RNA (with relaxed and stem-loop configurations), and the RNA binding proteins FUS, TDP-43, and hnRNPA1, each containing an LC domain, RNA recognition domain, and arginine-glycine-rich motifs. (b) LLPS promotes the formation of membraneless liquid droplets or hydrogels, a process which can be facilitated by the presence of RNA and low temperatures. The metastable property of liquid droplets is critical for the assembly and disassembly of many membraneless organelles, such as RNA granules, stress granules, the nucleolus, and nuclear speckles. Under pathological conditions, liquid droplets can transition into a solid-state structure or form amyloid fibrils, which are more stable and whose formation is likely irreversible.

Figure 4

Intracellular pathways targeted by disease pathogenesis in FTLD. The most common genetic mutation in FTLD is caused by (GGGGCC)_n hexanucleotide repeat expansion in the C9orf72 gene. C9orf72 mutations are known to generate RNA foci, which reside primarily in the nucleus. In addition, C9orf72 mutations use RAN-mediated translation to generate DPRs that disrupt the nuclear pore complex and interfere with liquid droplet formation. Finally, the protein product of C9orf72 has been detected in complex with WDR41 and SMCR8 as regulating the initiation of autophagy and the formation of autophagosomes. Several other FTLD genes, including SQSTM1, UBQLN2, OPTN, and VCP, have also been implicated in autophagy and the formation of autophagosomes. GRN, another major FTLD gene, encodes progranulin, a glycoprotein that can be either secreted and endocytosed or directly transported to the endolysosomal pathway where it regulates the formation, turnover, and possibly the exophagy of lysosomes. Abbreviations: DPR, dipeptide repeat; FTLD, frontotemporal lobar degeneration; MVB, multivesicular body; RAN, repeat-associated non-ATG.