An Autopsy Confirmed Case of Semantic Variant Primary Progressive Aphasia with Frontotemporal Lobar Degeneration-TDP type C

A 62-year-old man presented with a one-year history of word finding difficulty, impaired single word comprehension and personality changes including aggression, apathy and eating change. Brain MRIs showed severe atrophy in the left anterior temporal lobe. The clinical syndromic diagnosis was semantic variant primary progressive aphasia. He died at age 70 of pneumonia. At autopsy, transactive response DNA-binding protein (TDP) immunoreactive long dystrophic neurites were predominantly found in the cerebral cortices, which were compatible with frontotemporal lobar degeneration-TDP type C pathology.

Distinct Phospho-TDP-43 brain distribution in two cases of FTD, one associated with ALS / Distribuição cerebral distinta de fosfo-tdp-43 em dois casos de dft, um associado com ela

ABSTRACT. INTRODUCTION: TDP-43 is an intranuclear protein involved in many cellular processes. When altered, it shows a change in pattern of distribution, as well as in functioning, throughout the Central Nervous System structures. Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS) are examples of TDP-43 proteinopathy. These disorders form a clinical spectrum, with some patients having a pure cognitive disorder while others also exhibit motor features. METHODS: We studied two donated brains from patients with a diagnosis of Frontotemporal Dementia (FTD), one of which was associated with ALS (ALS-FTD). After fixation and macroscopic examinations, sample analyses were performed. Specific regions were chosen for the application of immunohistochemistry (IHC) with anti-Aß, AT8, anti-α-synuclein and anti-phospho-TDP-43. RESULTS: Both brains presented anti-phospho-TDP-43 positivity, but this was not equally distributed throughout the encephalic zones. In the FTD case, the studied brain presented phosphorylated TDP-43- in the frontal cortex, hippocampus, entorhinal cortex and mesencephalon; in the ALS-FTD case, the abnormal protein was also seen in the pons and medulla oblongata. The brain in the ALS-FTD case presented Aß and AT8 positivity in the hippocampus and entorhinal cortex (Braak I and II). DISCUSSION: The hypothesis supported by scientific literature that these neurodegenerative diseases can have the same etiology with distinct encephalic region involvement is corroborated by the present study.

RESUMO. INTRODUÇÃO: TDP-43 é uma proteína intranuclear envolvida em vários processos celulares. Essa molécula, quando alterada, mostra padrões de distribuição modificados, assim como de funcionamento, ao longo das estruturas do Sistema Nervoso Central. A Degeneração Lobar Frontotemporal (DLFT) e a Esclerose Lateral Amiotrófica (ELA) são dois exemplos de proteinopatia de TDP-43. Esses transtornos formam um espectro clínico, com alguns pacientes apresentando um transtorno cognitivo puro enquanto outros também apresentam disfunções motoras. MÉTODOS: Nós estudamos dois cérebros doados de pacientes com diagnóstico de Demência Frontotemporal (DFT), um dos quais se associava com ELA (ELA-DFT). Após fixação e exame macroscópico, foram realizadas análises de amostras. Regiões específicas foram escolhidas para aplicação de imunohistoquímica (IHQ) com anti-Aß, AT8, anti-α-sinucleina e anti-fosfo-TDP-43. RESULTADOS: Ambos os cérebros foram positivos para anti-fosfo-TDP-43, mas de forma não igualmente distribuida pelas regiões encefálicas. No caso DFT, o cérebro estudado apresentou TDP-43-fosforilada no córtex frontal, hipocampo, córtex entorrinal e mesencéfalo; no caso ELA-DFT, a proteína anormal também foi vista na ponte e no bulbo. O cérebro do caso ELA-DFT foi positivo para Aß e AT8 no hipocampo e no córtex entorrinal (Braak I e II). DISCUSSÃO: O presente estudo corrobora a hipótese atualmente sustentada pela literatura científica de que essas duas doenças neurodegenerativas possuem a mesma etiologia, mas acometem regiões encefálicas distintas.

La agregación de TDP-43 como posible blanco terapéutico contra la Esclerosis Lateral Amiotrófica / TDP-43 aggregation as a possible therapeutic target for Amyotrophic Lateral Sclerosis / Agregação de TDP-43 como um possível alvo terapêutico para a Esclerose Lateral Amiotrófica

Los agregados de TDP-43 representan una de las característica histopatológicas más importantes de varias enfermedades neurodegenerativas, entre las que se incluye la Esclerosis Lateral Amiotrófica (ELA). TDP-43 está localizada principalmente en el núcleo. Sin embargo, los pacientes afectados por ELA presentan agregados de TDP-43 en el citoplasma de las neuronas comprometidas, con lo que se despoja al núcleo de TDP-43 funcional. Aún se desconoce si la degeneración causada por la agregación de TDP-43 es debida a una toxicidad intrínseca de los agregados o a la pérdida de función de TDP-43 como consecuencia del vaciamiento del núcleo. Varias investigaciones, incluidas las de estos autores, indican que la pérdida de función es el factor fundamental responsable de la neurodegeneración observada en presencia de inclusiones de TDP-43. Por otro lado, aún no existen tratamientos efectivos para la ELA. Por lo tanto, es de crucial importancia conocer las bases moleculares que conllevan al desarrollo de la enfermedad, con el objetivo de encontrar posibles estrategias terapéuticas. Para ello, estos autores han desarrollado un modelo celular capaz de imitar la agregación de TDP-43 y sus consecuencias. Finalmente, se ha utilizado este modelo para analizar el efecto de diferentes compuestos capaces de degradar los agregados de TDP-43 y se ha demostrado que esta podría ser una estrategia terapéutica válida para la ELA.

TDP-43 inclusions are important histopathological features of various neurodegenerative disorders, including Amyotrophic Lateral Sclerosis (ALS). TDP-43 is mainly a nuclear protein, but it shuffles from the nucleus to the cytoplasm. In patients’ brains, TDP-43 is retained in the cytoplasm of the affected motorneurons to form insoluble aggregates, which results in TDP-43 nuclear clearance. There is still no consensus whether TDP-43-mediated neurodegeneration results from a gain or loss of function of the protein or a combination of both. The work from several laboratories, including this, points towards a strong loss of function component. On the other hand, there is no effective treatment or cure for ALS. Thus, there is obviously a need to find new therapeutic strategies for ALS. In order to gain new insights into the molecular mechanism of the disease, and with the aim of looking for new methodologies that can revert it, a cellular model of TDP-43 aggregation that can mimic the phenotypic consequences found in ALS patients has been developed. Finally, this model was used to search for compounds that can dissolve these aggregates, and it was shown that the clearance of TDP-43 aggregates could be a therapeutic strategy for ALS.

Os agregados proteicos TDP-43 são características histopatológicas importantes de muitas doenças neurodegenerativas, incluindo a Esclerose Lateral Amiotrófica (ALS). A proteína TDP-43 se localiza principalmente no núcleo, porém nos cérebros de indivíduos afetados, a proteína TDP-43 fica retida no citoplasma dos neurônios motores, o que leva a formação de agregados insolúveis, resultando em deposição nuclear. Ainda não existe um consenso se a neurodegeneração mediada por TDP43 é causada por ganho ou perda da função da proteína ou uma combinação de ambos. O trabalho de muitos laboratórios, bem como este trabalho, apontam para uma forte perda da função da proteína. Por outro lado, não existe um tratamento efetivo ou cura para a ALS. Portanto, existe uma grande necessidade de identificar novos tratamentos para a ALS. Para entender o mecanismo molecular da doença, e com o objetivo de identificar novas metodologias para reverter a doença, desenvolvemos o modelo celular de agregados de TDP-43, o qual mimetiza as consequências fenotípicas encontradas em pacientes com ALS. Por fim, utilizamos esse modelo para identificar compostos que podem dissolver os agregados, e demonstramos que a liberação de inclusões de TDP-43 poderiam ser usados como tratamentos para a ALS.

The Pathogenetic Role of TAR DNA Binding Protein (TDP-43) in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

The recent identification of the transactive response DNA binding protein with a molecular weight of 43 kDa (TDP-43) as the major pathological protein, in both amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin positive inclusions (FTLD-U), provides the new insight into understanding disease processes. The pathogenesis of both diseases is unclear, although they are related by having some overlap of symptoms and now by the shared histopathology of TDP-43 deposition. The number of degenerative diseases associated with TDP-43 has increased, leading to the new designation "TDP-43 proteinopathy". TDP-43 is a highly conserved protein ubiquitously expressed in many tissues including the central nervous system where it is present in neuronal and glial nuclei and to a lesser extent in the cytoplasm. Currently, TDP-43 has been implicated in regulating gene transcription and alternative splicing, in addition to maintaining mRNA stability. However, we still need to investigate the effects of posttranslational modifications of TDP-43, including phosphorylation, ubiquitination, and cleavage, on its regulation of various cellular processes. We review recently published studies of TDP-43 and its relationship to human disease with a special focus on ALS and FTLD-U. We conclude that the TDP-43 proteinopathies represent a novel class of neurodegenerative disorders and both ALS and FTLD-U are closely related conditions linked to similar mechanism of neurodegeneration.