Experimental studies in flies, mice, and humans suggest a significant role of impaired axonal transport in the pathogenesis of Alzheimer's disease (AD). The mechanisms underlying these impairments in axonal transport, however, remain poorly understood. Here we report that the Swedish familial AD mutation causes a standstill of the amyloid precursor protein (APP) in the axons at the expense of its reduced anterograde transport. The standstill reflects the perturbed directionality of the axonal transport of APP, which spends significantly more time traveling in the retrograde direction. This ineffective movement is accompanied by an enhanced association of dynactin-1 with APP, which suggests that reduced anterograde transport of APP is the result of enhanced activation of the retrograde molecular motor dynein by dynactin-1. The impact of the Swedish mutation on axonal transport is not limited to the APP vesicles since it also reverses the directionality of a subset of early endosomes, which become enlarged and aberrantly accumulate in distal locations. In addition, it also reduces the trafficking of lysosomes due to their less effective retrograde movement. Altogether, our experiments suggest a pivotal involvement of retrograde molecular motors and transport in the mechanisms underlying impaired axonal transport in AD and reveal significantly more widespread derangement of axonal transport pathways in the pathogenesis of AD.

• MeSH
• Alzheimer Disease * metabolism   genetics   pathology   MeSH
• Amyloid beta-Protein Precursor * genetics   metabolism   MeSH
• Axonal Transport * genetics   MeSH
• Axons metabolism   pathology   MeSH
• Dynactin Complex metabolism   genetics   MeSH
• Dyneins metabolism   MeSH
• Endosomes metabolism   genetics   MeSH
• Genetic Variation MeSH
• Humans MeSH
• Lysosomes metabolism   MeSH
• Mutation MeSH
• Mice MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; glycyl-tRNA synthetase (GARS), dynactin 1 (DCTN1), small heat shock 27 kDa protein 1 (HSPB1), small heat shock 22 kDa protein 8 (HSPB8), Berardinelli-Seip congenital lipodystrophy (BSCL2) and senataxin (SETX). In addition a mutation in the (VAMP)-associated protein B and C (VAPB) was found in several Brazilian families with complex and atypical forms of autosomal dominantly inherited motor neuron disease. We have investigated the distribution of mutations in these seven genes in a cohort of 112 familial and isolated patients with a diagnosis of distal motor neuropathy and found nine different disease-causing mutations in HSPB8, HSPB1, BSCL2 and SETX in 17 patients of whom 10 have been previously reported. No mutations were found in GARS, DCTN1 and VAPB. The phenotypic features of patients with mutations in HSPB8, HSPB1, BSCL2 and SETX fit within the distal HMN classification, with only one exception; a C-terminal HSPB1-mutation was associated with upper motor neuron signs. Furthermore, we provide evidence for a genetic mosaicism in transmitting an HSPB1 mutation. This study, performed in a large cohort of familial and isolated distal HMN patients, clearly confirms the genetic and phenotypic heterogeneity of distal HMN and provides a basis for the development of algorithms for diagnostic mutation screening in this group of disorders.

• MeSH
• Electrophysiology MeSH
• Phenotype MeSH
• Genotype MeSH
• Haplotypes MeSH
• Hereditary Sensory and Motor Neuropathy * genetics   physiopathology   MeSH
• Humans MeSH
• Chromosomes, Human, Pair 11 genetics   MeSH
• Mutation, Missense * MeSH
• Mosaicism MeSH
• Neoplasm Proteins genetics   MeSH
• Protein Serine-Threonine Kinases genetics   MeSH
• HSP27 Heat-Shock Proteins MeSH
• Heat-Shock Proteins genetics   MeSH
• GTP-Binding Protein gamma Subunits genetics   MeSH
• RNA Helicases genetics   MeSH
• Pedigree MeSH
• Base Sequence MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Research Support, Non-U.S. Gov't MeSH