Inside out: the role of nucleocytoplasmic transport in ALS and FTLD

Abstract

Neurodegenerative diseases are characterized by the presence of protein inclusions with a different protein content depending on the type of disease. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are no exceptions to this common theme. In most ALS and FTLD cases, the predominant pathological species are RNA-binding proteins. Interestingly, these proteins are both depleted from their normal nuclear localization and aggregated in the cytoplasm. This key pathological feature has suggested a potential dual mechanism with both nuclear loss of function and cytoplasmic gain of function being at play. Yet, why and how this pathological cascade is initiated in most patients, and especially sporadic cases, is currently unresolved. Recent breakthroughs in C9orf72 ALS/FTLD disease models point at a pivotal role for the nuclear transport system in toxicity. To address whether defects in nuclear transport are indeed implicated in the disease, we reviewed two decades of ALS/FTLD literature and combined this with bioinformatic analyses. We find that both RNA-binding proteins and nuclear transport factors are key players in ALS/FTLD pathology. Moreover, our analyses suggest that disturbances in nucleocytoplasmic transport play a crucial initiating role in the disease, by bridging both nuclear loss and cytoplasmic gain of functions. These findings highlight this process as a novel and promising therapeutic target for ALS and FTLD.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1586-5) contains supplementary material, which is available to authorized users.

Mechanisms of protein toxicity in neurodegenerative diseases

“…In addition to the transcriptional and epigenetic alterations, nucleocytoplasmic transport defects have emerged as one of the principal nuclear dysfunctions manifested in neurodegenerative diseases such as ALS/FTD, HD, and AD [19, 50]. The mechanisms by which nucleocytoplasmic transport becomes disrupted range from sequestration of nuclear pore complex (NPC) molecules by toxic RNA or proteins [19, 51–56] to direct blockage of nuclear pores by toxic disease proteins [57].…”

“…The mechanisms by which nucleocytoplasmic transport becomes disrupted range from sequestration of nuclear pore complex (NPC) molecules by toxic RNA or proteins [19, 51–56] to direct blockage of nuclear pores by toxic disease proteins [57]. Some excellent reviews on this topic have recently been published, which we recommend for detailed discussion [19, 50]. …”

Expansión anormal de hexanucleótido en gen C9orf72 en una familia con demencia frontotemporal y cuadros asociados

“…Entre los mecanismos propuestos donde existe más evidencia figura la ganancia de función tóxica, ya sea por moléculas de ARNs como de proteínas 6,7 . La toxicidad por ARNs se podría explicar por la transcripción de las dos hebras de la repetición G4C2 y G2C4 (hebras sentido y antisentido), a diferencia de la condición normal en que sólo se transcribe la hebra molde (antisentido).…”

“…La toxicidad por ARNs se podría explicar por la transcripción de las dos hebras de la repetición G4C2 y G2C4 (hebras sentido y antisentido), a diferencia de la condición normal en que sólo se transcribe la hebra molde (antisentido). Esto determina la formación de focos de ARN sentido y antisentido en todo el sistema nervioso central 6,7 . La toxicidad por proteínas se podría explicar por traducción no convencional en distintos marcos de lectura de los mismos ARNs producidos por transcripción de las dos hebras de la repetición G4C2 y G2C4, lo que lleva a formación de inclusiones de dipéptidos 7 .…”

“…La toxicidad por proteínas se podría explicar por traducción no convencional en distintos marcos de lectura de los mismos ARNs producidos por transcripción de las dos hebras de la repetición G4C2 y G2C4, lo que lleva a formación de inclusiones de dipéptidos 7 . La acumulación de ARN tóxico y la formación de dipéptidos inducirían disfunción del transporte núcleo-citoplasmático y estrés celular 6,7 . Final- Diagnóstico genético en DFT y ELA Determinar la causa última que explica una condición hereditaria como esta es importante para la toma de decisiones concernientes al paciente y familia, incluyendo portadores asintomáticos interesados en conocer su propia información 8 .…”