The microtubule-actin crosslinking factor 1 (MACF1) is a ubiquitous cytoskeletal linker protein with multiple spliced isoforms expressed in different tissues. The MACF1a isoform contains microtubule and actin binding regions and is expressed at high levels in the nervous system. Macf1−/− mice are early embryonic lethal and hence the role of MACF1 in the nervous system could not be determined. We have specifically knocked out MACF1a in the developing mouse nervous system using Cre/loxP technology. Mutant mice died within 24–36 hrs after birth of apparent respiratory distress. Their brains displayed a disorganized cerebral cortex with a mixed layer structure, heterotopia in the pyramidal layer of the hippocampus, disorganized thalamocortical and corticofugal fibers, and aplastic anterior and hippocampal commissures. Embryonic neurons showed a defect in traversing the cortical plate. Our data suggest a critical role for MACF1 in neuronal migration that is dependent on its ability to interact with both microfilaments and microtubules.

Neurofilament light gene mutations have been linked to a subset of patients with Charcot-Marie-Tooth disease, the most common inherited motor and sensory neuropathy. We have previously shown that Charcot-Marie-Tooth-linked mutant neurofilament light assembles abnormally in non-neuronal cells. In this study, we have characterized the effects of expression of mutant neurofilament light proteins on axonal transport in a neuronal cell culture model. We demonstrated that the Charcot-Marie-Tooth-linked neurofilament light mutations: (i) affect the axonal transport of mutant neurofilaments; (ii) have a dominant-negative effect on the transport of wild-type neurofilaments; (iii) affect the transport of mitochondria and the anterograde axonal transport marker human amyloid precursor protein; (iv) result in alterations of retrograde axonal transport and (v) cause fragmentation of the Golgi apparatus. Increased neuritic degeneration was observed in neuronal cells overexpressing neurofilament light mutants. Our results suggest that these generalized axonal transport defects could be responsible for the neuropathy in Charcot-Marie-Tooth disease.

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Protein accumulation is a hallmark of many neurodegenerative disorders. In Alzheimer's disease (AD), a hyperphosphorylated form of the protein tau (p-tau) forms intracellular inclusions known as neurofibrillary tangles. Deposits of p-tau have also been found in the brains of patients with Down's syndrome, supranuclear palsy, and prion disease. Mutations in tau have been causally associated with at least one inherited neurologic disorder, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), implying that tau abnormalities by themselves can be a primary cause of degenerative diseases of the CNS. Removal of these p-tau species may occur by both chaperone-mediated refolding and degradation. In this issue of the JCI, Dickey and colleagues show that a cochaperone protein, carboxyl terminus of Hsp70-interacting protein (CHIP), in a complex with Hsp90 plays an important role in the removal of p-tau (see the related article beginning on page 648). Pharmacologic manipulation of Hsp90 may be used to alleviate p-tau accumulation in disease.

J. Neurochem.(2008) 104, 1536–1552. Abstract Charcot‐Marie‐Tooth disease (CMT) is an inherited peripheral neuropathy that has been linked to mutations in multiple genes. Mutations in the neurofilament light (NFL) chain gene lead to the CMT2E form whereas mutations in the myotubularin‐related protein 2 and 13 (MTMR2 and MTMR13) genes lead to the CMT4B form. These two forms share characteristic pathological hallmarks on nerve biopsies including concentric sheaths (‘onion bulbs’) and, in at least one case, myelin loops. In addition, MTMR2 protein has been shown to interact physically with both NFL and MTMR13. Here, we present evidence that CMT‐linked mutations of MTMR2 can cause NFL aggregation in a cell line devoid of endogenous intermediate filaments, SW13vim−. Mutations in the protein responsible for X‐linked myotubular myopathy (myotubularin, MTM1) also induced NFL abnormalities in these cells. We also show that two MTMR2 mutant proteins, G103E and R283W, are unable to form dimers and undergo phosphorylation in vivo, implicating impaired complex formation in myotubularin‐related pathology.