Table 3.
Karyopherin abnormalities in neurodegenerative proteinopathies
| Karyopherin | Pathogenesis | References |
|---|---|---|
|
ALS/FTD-TDP | ||
| KPNA2 | Reduced levels in FTD-TDP frontal cortex; accumulating TDP-43 causes cytoplasmic mislocalization in a Drosophila model of C9ALS/FTD. | Chou et al.,15 Solomon et al.,16 Nishimura et al.54 |
| KPNA4 | Accumulating TDP-43 causes cytoplasmic mislocalization in a Drosophila model of C9ALS/FTD; depletion of KPNA directly contributes to impaired nuclear import and cytoplasmic accumulation of TDP-43. | Chou et al.,15 Solomon et al.,16 Park et al.103 |
| XPO1 | In ALS models, XPO1 inhibition showed neuroprotective effects against C9orf72-related disease. | Zhang et al.21 |
| CAS | Reduced levels in FTD-TDP frontal cortex; knockdown of CAS dysregulates the import of TDP-43. | Nishimura et al.54 |
| KPNB1 | Reduced levels in spinal cords of patients with ALS; irregular and disrupted nuclear staining in sporadic ALS with TDP-43; depletion of KPNB1 directly contributes to impaired nuclear import and cytoplasmic accumulation of TDP-43; ALS-related mutations in FUS reduce its sensitivity to the chaperone activity of KPNB1, ultimately leading to increased phase separation. | Solomon et al.,16 Hofweber et al.,17 Yamashita et al.,78 Aizawa et al.,80 Park et al.103 |
| TNPO 1 | ALS related mutations in FUS reduce its sensitivity to the chaperone activity of TNPO1, ultimately leading to increased phase separation. | Hofweber et al.17 |
|
| ||
|
Alzheimer’s disease/FTD-Tau | ||
| KPNA2 | Accumulation and aggregation of KPNA2 is found in neurofibrillary tangles and Hirano bodies of hippocampal CA1 neurons of Alzheimer’s disease patients. | Lee et al.,56 Carter57 |
| KPNA3 | Abnormally upregulated levels of KPNA3 found in cDNA microarray studies of Alzheimer’s disease human brains. | Wang et al.55 |
| KPNA6 | Upregulated KPNA6 identified in association with small non-coding RNAs. | Roy et al.58 |
| KPNB1 | Found within cytoplasmic granules in hippocampal neurons in Alzheimer’s disease cases and co-localizes with hyperphosphorylated tau. | Nuovo et al.,59 Sheffield and Mirra107 |
| KPNB2 | Found in cytoplasmic granules in hippocampal neurons and in tangle-bearing cells of Alzheimer’s disease cases. | Sheffield and Mirra107 |
| XPO1 | Tau‐induced nuclear envelope invaginations sequester XPO1 in a Drosophila model of tauopathy. | Cornelison et al.108 |
|
| ||
|
Synucleinopathies | ||
| KPNA2 | Targeted knockdown linked to nuclear aggregation of α-syn; substrate of LRRK2/PARK8. | Ma et al.,62 Han et al.64 |
| KPNA3 | α-Syn mediated cytotoxicity involves interaction with KPNA3 | Büttner et al.137 |
| KPNA6 | Substrate of LRRK2/PARK8 | Han et al.64 |
| KPNA7 | Lewy body formation triggers alterations in the expression level of KPNA7. | Ma et al.62 |
| XPO1 | FBXO7/PARK15 was found mislocalized together with α-syn in Lewy bodies, Lewy neurites and cytoplasmic inclusions in glial cells in both Parkinson’s disease and MSA cases; Lewy body formation triggers the alterations in the expression level. | Ma et al.,62 Zhao et al.142 |
| KPNB1 | Alterations in the expression level of Parkinson’s disease patients with a triplication in the SNCA locus encoding α-syn. | George et al.,65 Devine et al.135 |
| KPNB2 | Mutant DJ-1/PARK7 was shown to interact with KPNB2 in an oxidative stress-dependent manner leading to its mislocalization. | Björkblom et al.63 |
| KPNB3 | α-Syn-mediated cytotoxicity lead to upregulation of KPNB3. | Zhou et al.61 |
| KPNA1 | Target of mHTT in genomics and proteomics study of transgenic mice expressing mHTT. | Langfelder et al.159 |
|
| ||
|
Huntington’s disease | ||
| KPNA2 | mHTT-transfected mouse neurons cause aggregation of mHTT and KPNA2/KPNA4. Some KPNA2/4 aggregates were associated with mHTT aggregates; target of mHTT in genomics and proteomics study of transgenic mice expressing mHTT. | Woerner et al.,70 Langfelder et al.159 |
| KPNA3 | Target of mHTT in genomics and proteomics study of transgenic mice expressing mHTT. | Langfelder et al.159 |
| KPNA4 | mHTT-transfected mouse neurons cause aggregation of mHTT and KPNA2/KPNA4. Some KPNA2/4 aggregates were associated with mHTT aggregates; target of mHTT in genomics and proteomics study of transgenic mice expressing mHTT. | Woerner et al.,70 Langfelder et al.159 |
| KPNA6 | Binding partner of mHTT in mouse brain expressing mHTT expanded with 97 polyQ; target of mHTT in genomics and proteomics study of transgenic mice expressing mHTT. | Shirasaki et al.,158 Langfelder et al.159 |
| KPNB1 | Binding partner of mHTT in mouse brain expressing mHTT expanded with 97 polyQ; Target of mHTT in genomics and proteomics study of transgenic mice expressing mHTT. | Shirasaki et al.,158 Langfelder et al.159 |
| KPNB2 | Target of mHTT in genomics and proteomics study of transgenic mice expressing mHTT. | Langfelder et al.159 |
| XPO7 | Binding partner of mHTT in mouse brain expressing mHTT expanded with 97 polyQ. | Shirasaki et al.158 |
| CAS | Binding partner of mHTT in mouse brain expressing mHTT expanded with 97 polyQ. | Shirasaki et al.158 |
MSA = multiple system atrophy.