Förderung 2016

“Role of nuclear pore complex dysfunction in cell cycle-related neurodegeneration of the aging and diseased CNS”

Summary:

Perturbances in nucleo-cytoplasmic protein trafficking contribute to cellular pathology in several proteinopathies of the CNS including amyotrophic lateral sclerosis (ALS). Cytotoxicity of aggregated proteins is compartment-specific even at identical biochemical structure, as exemplified for ß-amyloid, mutated huntingtin, or TDP-43 [1,2]. As a putative novel class of molecules involved, we recently identified disturbances in the subcellular distribution of cell cycle (CC) regulatory Cdk4 and Cdk5, with Cdk5 featuring a striking nuclear reduction in α-motor neurons of hSOD1G93A transgenic mice, an animal model of familiar ALS. Nuclear Cdk5 is essential to maintain a continuous postmitotic state in neurons, whereas its nuclear depletion contributes to neuronal dysfunction and death by re-initiation of unscheduled, abortive CC activity [3-6].

Subcellular mislocalization of G1-regulatory Cdk4/5 is thus suggestive to cause cytotoxicity similar to TDP-43 and β-amyloid in ALS and Alzheimer pathology, respectively, through detrimental CC re-activation in neurons. The cellular and molecular cues regulating subcellular CC protein compartmentalization, however, are not yet understood. We assume that a dysfunction of the nuclear pore complex (NPC), the essential structure in mediating bidirectional trafficking and proper distribution of most proteins within the cell [7], is causal for CC protein displacement and related neuronal death observed in CNS aging and pathology. As a mechanism structurally and functionally associated with the NPC, we will further investigate nuclear lamina dispersion as a function of neurosenescence and ALS pathology.

In summary, the project will elucidate the interplay between nuclear membrane dysfunction and detrimental consequences of ‘replicative reprogramming’ in the context of CNS aging and exemplify it for ALS pathology. Therapeutic interference with pathomechanisms involved might open novel targets to prevent or halt age-related dysfunction and neurodegeneration in different disease entities, and carry fundamental and clinical relevance.

References:

1. Woerner AC, Frottin F, Hornburg D, Feng LR, Meissner F, Patra M, Tatzelt J, Mann M, Winklhofer KF, Hartl FU, Hipp MS. (2016) Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA. Science 351(6269):173-176.
2. Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD (2015) The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525(7567):56-61. 
3. Zhang J, Cicero SA, Wang L, Romito-DiGiacomo RR, Yang Y, Herrup K (2008) Nuclear localization of Cdk5 is a key determinant in the postmitotic state of neurons. Proc Natl Acad Sci U S A. 105(25):8772–8777.
4. Zhang J, Li H, Herrup K (2010) Cdk5 nuclear localization is p27-dependent in nerve cells: implications for cell cycle suppression and caspase-3 activation. J Biol Chem 285(18):14052-61.
5. Zhang J, Li H, Yabut O, Fitzpatrick H, D'Arcangelo G, Herrup K (2010) Cdk5 suppresses the neuronal cell cycle by disrupting the E2F1-DP1 complex. J Neurosci 30(15):5219-28. 
6. Zhang J, Herrup K (2011) Nucleocytoplasmic Cdk5 is involved in neuronal cell cycle and death in post-mitotic neurons. Cell Cycle 10(8):1208-1214.
7. D’Angelo MA, Hetzer MW (2008) Structure, dynamics and function of the nuclear pore complexes. Trends Cell Biol 18(10):456-66.