Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies

Mackenzie, Ian R.; Neumann, Manuela

doi:10.1111/jnc.13588

Cited by 290 publications

(303 citation statements)

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confidence: 99%

“…This has led to speculation that pathogenesis in the vast majority of ALS cases may be mechanistically linked directly or indirectly to TDP-43 pathology (7, 11). Intriguingly, TDP-43 pathology is also a common hallmark of certain forms of FTD where the pathology is found in the brain (5,7,12).Missense mutations (P497H, P497S, P506T, P509S, or P525S) in ubiquilin 2 (UBQLN2) were identified as the cause of X-linked dominant ALS-FTD (13). The afflicted individuals had abnormal inclusions in neurons of the hippocampus and TDP-43 pathology in spinal motor neurons.…”

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Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS–FTD-linked UBQLN2 mutations

Chang

Kovlyagina

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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Missense mutations in ubiquilin 2 (UBQLN2) cause ALS with frontotemporal dementia (ALS-FTD). Animal models of ALS are useful for understanding the mechanisms of pathogenesis and for preclinical investigations. However, previous rodent models carrying UBQLN2 mutations failed to manifest any sign of motor neuron disease. Here, we show that lines of mice expressing either the ALS-FTD-linked P497S or P506T UBQLN2 mutations have cognitive deficits, shortened lifespans, and develop motor neuron disease, mimicking the human disease. Neuropathologic analysis of the mice with end-stage disease revealed the accumulation of ubiquitinated inclusions in the brain and spinal cord, astrocytosis, a reduction in the number of hippocampal neurons, and reduced staining of TAR-DNA binding protein 43 in the nucleus, with concomitant formation of ubiquitin + inclusions in the cytoplasm of spinal motor neurons. Moreover, both lines displayed denervation muscle atrophy and age-dependent loss of motor neurons that correlated with a reduction in the number of large-caliber axons. By contrast, two mouse lines expressing WT UBQLN2 were mostly devoid of clinical and pathological signs of disease. These UBQLN2 mouse models provide valuable tools for identifying the mechanisms underlying ALS-FTD pathogenesis and for investigating therapeutic strategies to halt disease.A LS is a progressive neurodegenerative disorder associated with loss of upper and lower motor neurons (1, 2). The disease usually manifests in the fifth decade of life, but can occur as early as the late teens. Its hallmark symptoms are progressive muscle weakness, which usually leads to death between 3 and 5 y after first diagnosis. Some patients with ALS also develop frontotemporal dementia (FTD). Genetic findings have linked mutations in different genes to the range of symptoms seen in ALS (3, 4).A common pathologic feature in nearly all ALS cases (∼97%), including all sporadic and most familial cases, is a reduction in TAR-DNA binding protein 43 (TDP-43) in the nucleus and its accumulation in ubiquitin + inclusions in the cytoplasm of spinal motor neurons (5-8). The few exceptions where this pathology is not seen are in ALS cases linked to mutations in the SOD1 and FUS genes (7-10). This has led to speculation that pathogenesis in the vast majority of ALS cases may be mechanistically linked directly or indirectly to TDP-43 pathology (7, 11). Intriguingly, TDP-43 pathology is also a common hallmark of certain forms of FTD where the pathology is found in the brain (5,7,12).Missense mutations (P497H, P497S, P506T, P509S, or P525S) in ubiquilin 2 (UBQLN2) were identified as the cause of X-linked dominant ALS-FTD (13). The afflicted individuals had abnormal inclusions in neurons of the hippocampus and TDP-43 pathology in spinal motor neurons. Additional UBQLN2 mutations have now been identified, and interestingly, like the original mutations, encode missense mutations in the central domain of UBQLN2 protein (14-16). The function of the central domain of UBQLN2 is beginning to em...

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confidence: 99%

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confidence: 99%

Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS–FTD-linked UBQLN2 mutations

Chang

Kovlyagina

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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“…Most cases of frontotemporal lobar degeneration (FTLD) can be classified into three molecular subtypes: (1) FTLD with tau-immunoreactive inclusions (FTLDtau), a heterogeneous group of disorders, examples of which include corticobasal degeneration (CBD), Pick's disease (PiD), and progressive supranuclear palsy (PSP), (2) FTLD with transactive response (TAR) DNA-binding protein 43 (TDP-43)-immunoreactive inclusions (FTLD-TDP), and (3) FTLD with 'fused in sarcoma' (FUS)-immunoreactive inclusions (FTLD-FUS) [42]. In all of these disorders, abnormally aggregated proteins result in the formation of phosphorylated 'signature' neuronal cytoplasmic inclusions (NCI), FUS protein in FTLD-FUS being additionally hypomethylated [48], most abundantly in the frontal and temporal cortex [15,29,52].…”

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confidence: 99%

Neuronal cytoplasmic inclusions in tau, TDP-43, and FUS molecular subtypes of frontotemporal lobar degeneration share similar spatial patterns

Armstrong¹

2017

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A b s t r a c t The 'prion-like' transfer of pathogenic proteins may play a role in the pathogenesis of frontotemporal lobar degeneration (FTLD). Propagation of such proteins along anatomical pathways may give rise to specific spatial patterns of the 'signature' neuronal cytoplasmic inclusions (NCI) characteristic of these disorders. Hence, the spatial patterns of the NCI were compared in three molecular subtypes of FTLD: (1) two variants of FTLD-tau, viz. corticobasal degeneration (CBD) and Pick's disease (PiD), (2) FTLD with transactive response (TAR) DNA-binding protein 43 (TDP-43)-immunoreactive inclusions (FTLD-TDP), and (3) FTLD with 'fused in sarcoma' (FUS)-immunoreactive inclusions (FTLD-FUS). Regardless of molecular pathology, the NCI in the frontal and temporal cortex were most frequently aggregated into clusters, the clusters being regularly distributed parallel to the pia mater. In a significant propor FTLD-TDP and FTLD-FUS than in FTLD-tau.

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“…RNA-binding protein TLS (translocated in liposarcoma)/ FUS (fused in sarcoma) is a causative gene for amyotrophic lateral sclerosis (ALS) [1,2] and frontotemporal lobar degeneration (FTLD) [3]. Clinical symptoms of ALS are characterized by the impairment of up and lower motor neurons, indicate muscle atrophy, and gradually spread to the muscle of whole body including respiratory system.…”

Section: Introductionmentioning

confidence: 99%

Biotin-Lys-His Blocks Aggregation of RNA-binding Protein TLS, a Cause of Amyotrophic Lateral Sclerosis

Ueda¹

2017

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RNA-binding protein TLS/FUS is a causative gene for amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TLS mutations induce the propensity of TLS to form aggregates in motor neurons causing neuronal degenerative lesions to their necrosis. TLS is prone to be precipitated in high concentration around 10 mg/ml, while mutated TLS is suspected to be precipitated even lower or physiological concentration in the motor neurons. An unidentified agent from infections would cause formation of the precipitation of TLS through their surface antigens. The precipitation driven with agents might be attribute to a small compound appeared on the surface. Biotinylated isoxazole (BISOX) has been reported to be precipitated with divergent RNA-binding proteins including TLS in nuclear extracts of cultured mammalian cells. We have published a molecular model for crystal formation of BISOX with TLS providing a plat form for searching novel regulators to precipitate TLS in neuronal disorders. Because BISOX is an artificial compound, we have further explored to obtain naturally occurring agents to induce the TLS precipitation and generated a conceivable biological compound, biotin-Lys-His (BLH). We have examined the precipitation of BLH with HeLa cell nuclear extract, but did not detect any TLS signal. Then, we add BLH to reaction of BISOX with TLS, and serendipitously observed a robust inhibitory effect of BLH on the formation of crystal of BISOX with TLS. We employed in silico analysis to show how BLH blocks the crystal formation of BISOX with TLS. The computational analysis of the events presented a model that BLH should be incorporated into the crystal formation of BISOX but some steric hindrance placed by BLH blocks growing of the crystal of BISOX and TLS. These results provide the potentiality that BLH should block the aggregate formation of TLS in ALS, leading to a seed for drug discovery against ALS, although it needs future endeavor to find more compounds to have effect on the TLS aggregation.

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Molecular neuropathology of frontotemporal dementia: insights into disease mechanisms from postmortem studies

Cited by 290 publications

References 172 publications

Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS–FTD-linked UBQLN2 mutations

Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS–FTD-linked UBQLN2 mutations

Neuronal cytoplasmic inclusions in tau, TDP-43, and FUS molecular subtypes of frontotemporal lobar degeneration share similar spatial patterns

Biotin-Lys-His Blocks Aggregation of RNA-binding Protein TLS, a Cause of Amyotrophic Lateral Sclerosis

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