Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. We previously showed that the expression of dynactin 1, an axon motor protein regulating retrograde transport, is markedly reduced in spinal motor neurons of sporadic ALS patients, although the mechanisms by which decreased dynactin 1 levels cause neurodegeneration have yet to be elucidated. The accumulation of autophagosomes in degenerated motor neurons is another key pathological feature of sporadic ALS. Since autophagosomes are cargo of dynein/dynactin complexes and play a crucial role in the turnover of several organelles and proteins, we hypothesized that the quantitative loss of dynactin 1 disrupts the transport of autophagosomes and induces the degeneration of motor neuron. In the present study, we generated a Caenorhabditis elegans model in which the expression of DNC-1, the homolog of dynactin 1, is specifically knocked down in motor neurons. This model exhibited severe motor defects together with axonal and neuronal degeneration. We also observed impaired movement and increased number of autophagosomes in the degenerated neurons. Furthermore, the combination of rapamycin, an activator of autophagy, and trichostatin which facilitates axonal transport dramatically ameliorated the motor phenotype and axonal degeneration of this model. Thus, our results suggest that decreased expression of dynactin 1 induces motor neuron degeneration and that the transport of autophagosomes is a novel and substantial therapeutic target for motor neuron degeneration.
Highlights
Autophagy is one of the major cellular systems that regulate protein degradation and organelle turnover in physiological and pathological conditions [1], and it is an essential quality control system for proteins in post-mitotic neurons that need to eliminate abnormal proteins and organelles for their proper function and survival [2,3]
Recent studies indicate that the dysregulation of autophagy in motor neurons is a pivotal event in amyotrophic lateral sclerosis (ALS) [8,10]; we investigated the relationship between decreased dynactin 1 expression and autophagy in sporadic ALS (SALS)
Quantitative analysis revealed that anti-light chain 3 (LC3) immunoreactivity was significantly increased in the spinal motor neurons of SALS patients (p,0.0001) (Fig. 1D), and was inversely correlated with the decreased mRNA levels of DCTN1 (Fig. 1E) and cell size (Fig. 1F) in the motor neurons of SALS patients, indicating that the dysregulation of autophagy is associated with the decreased expression of dynactin 1 in SALS
Summary
Autophagy is one of the major cellular systems that regulate protein degradation and organelle turnover in physiological and pathological conditions [1], and it is an essential quality control system for proteins in post-mitotic neurons that need to eliminate abnormal proteins and organelles for their proper function and survival [2,3]. Electron microscopy of the motor neurons of ALS patients shows an increased number of autophagosomes surrounded by a doublemembrane that contain sequestered cytoplasmic organelles, e.g., mitochondria [8]. These observations suggest the possibility that autophagy is upregulated to protect neurons from increased amounts of aggregated proteins and/or damaged organelles, it is possible that the accumulation of autophagosomes due to dysregulated autophagy leads to neurodegeneration. One possible mechanism for the accumulation of autophagosomes in degenerated neurons is the disruption of the cellular transport system, given that autophagosomes are cargo that moves bidirectionally along microtubules, which is powered by the kinesin family of motor proteins and dynein/dynactin complexes [11,12]. We hypothesized that the decreased expression of dynactin 1 results in the disrupted transport of autophagosomes and attenuates the protective effects of autophagy against neurodegeneration
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