Fig. 1

Molecular mechanisms of NF aggregation. The scheme shows the principal pathways triggering neurofilament (NF) aggregation in the neurodegenerative diseases listed in Tables 1 and 3. NF subunits can undergo hyper-phosphorylation and accumulation due to pathological mutations in NF-coding genes (inner circle). Alternatively, NF accumulation can be caused by damaging mutations in genes directly involved in NF metabolism such as factors regulating NF turnover and degradation; gigaxonin is shown as an example (intermediate circle). Lastly, NF aggregation can be the result of the dysregulation in cellular signaling pathways converging on NF metabolism such as specific protein kinase cascades (outer circle). While the first two mechanisms are at the root of rare neurological disorders like giant axon neuropathy (GAN) and Charcot-Marie-Tooth (CMT) syndromes, the latter is likely to explain NF aggregation in the more common neurodegenerative diseases