Nuclear pore complexes - a doorway to neural injury in neurodegeneration

Abstract

The genetic underpinnings and end-stage pathological hallmarks of neurodegenerative diseases are increasingly well defined, but the cellular pathophysiology of disease initiation and propagation remains poorly understood, especially in sporadic forms of these diseases. Altered nucleocytoplasmic transport is emerging as a prominent pathomechanism of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer disease, frontotemporal dementia and Huntington disease. The nuclear pore complex (NPC) and interactions between its individual nucleoporin components and nuclear transport receptors regulate nucleocytoplasmic transport, as well as genome organization and gene expression. Specific nucleoporin abnormalities have been identified in sporadic and familial forms of neurodegenerative disease, and these alterations are thought to contribute to disrupted nucleocytoplasmic transport. The specific nucleoporins and nucleocytoplasmic transport proteins that have been linked to different neurodegenerative diseases are partially distinct, suggesting that NPC injury contributes to the cellular specificity of neurodegenerative disease and could be an early initiator of the pathophysiological cascades that underlie neurodegenerative disease. This concept is consistent with the fact that rare genetic mutations in some nucleoporins cause cell-type-specific neurological disease. In this Review, we discuss nucleoporin and NPC disruptions and consider their impact on cellular function and the pathophysiology of neurodegenerative disease.

Fig. 1 |. Overview of nuclear pore complex structure and subcomplexes.

The main subcomplexes of the nuclear pore complex are the cytoplasmic ring and filaments, the outer ring, the inner ring, the transmembrane ring, the central channel and the nuclear basket. Each subcomplex consists of multiple nucleoporins, listed as bullet points for each subcomplex. Adapted from REF., Springer Nature Ltd.

Fig. 2 |. Alterations in the nuclear pore complex and nucleocytoplasmic transport in neurodegenerative diseases.

a | Under physiological conditions, mRNA and protein are transported out of and into the nucleus via the nuclear pore complex (NPC). b | In Huntington disease (HD), import and export through the NPC is impaired, leading to impaired protein import and mRNA export. In addition, a subset of nucleoporins (Nups) and nuclear pore-associated proteins with roles in nucleocytoplasmic transport (NCT) are present in nuclear and cytoplasmic aggregates (TABLE 1). c | In amyotrophic lateral sclerosis (ALS), specific Nups (TABLE 1) are reduced from neuronal NPCs, in a manner dependent on CHMP7 and the ESCRT-III complex, with no change in overall NPC number or structure. Consequently, import and export through the NPC is impaired. Moreover, a handful of Nups and nucleocytoplasmic transport proteins (TABLE 1) accumulate in the cytoplasm via unknown mechanisms. d | In Alzheimer disease (AD) and frontotemporal dementia (FTD), cytoplasmic and perinuclear accumulation of a small number of Nups (TABLE 1) occurs. In addition, accumulation of mRNA within nuclear membrane invaginations and impairments in protein import have been described, although the biological implications are unknown and the mechanistic link between all these pathologies remains unclear.

Fig. 3 |. Pathological progression of changes to the nuclear pore complex and nucleocytoplasmic transport in amyotrophic lateral sclerosis.

Aberrant nuclear retention of the ESCRT-III-associated protein CHMP7 initiates nuclear pore injury characterized by the reduction in specific nucleoporins (Nups) from the nuclear pore complex (NPC), leading to an altered composition of the NPC (1). Disruption of the NPC in this way alters functional nucleocytoplasmic transport (NCT) (2), which ultimately leads to loss of TAR DNA-binding protein 43 (TDP43) function within the nucleus and translocation of TDP43 from the nucleus to the cytoplasm (3). Impaired NCT might result in cytoplasmic accumulation of TDP43, Nups and nuclear transport receptors in end-stage disease (4). Impaired nuclear import might then inhibit restoration of the NPC composition and integrity (5), thereby exacerbating the process.