Does clinical evidence for lower motor neuron dysfunction support prion-like spreading in ALS?
In a recent, impressive article, Teruhiko Sekiguchi et al. (1) hypothesize that misfolded proteins accumulating in some neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), can cause aggregation of their native counterparts through a mechanism similar to the infectious prion protein's induction of a pathogenic conformation onto its normal cellular isoform. Recent in vitro studies have indicated that newly formed aggregates of TAR DNA-binding protein 43 as well as superoxide dismutase 1 (SOD1) can act as templates for the subsequent misfolding of the respective native proteins, and that the misfolded proteins can be intercellularly transferred in cultured cells (2).
Neurodegeneration in ALS typically begins focally and then spreads spatiotemporally until neurons of the respiratory system are lost. Some researchers, therefore, suggest that ALS pathology is similarly initiated at a single site and spreads via cell-to-cell transmission of prion-like pathogenic conformers in a 'single seed and simple propagation' model of ALS (2). Assuming that ALS progresses according to the proposed model, ALS lesions will spread contiguously along the spinal segments. Using needle electromyography (EMG), Sekiguchi et al. analyzed abnormal spontaneous activity of pairs of muscles innervated from different spinal segments in patients with early-stage sporadic ALS. They found that abnormal lower motor neuron activity showed a noncontiguous pattern in many ALS patients, suggesting that this skipping pattern of rostrocaudal spread does not support the 'single seed' hypothesis. Instead, they proposed a 'multifocal hits and local propagation' hypothesis. In their article, however, they do not present the data to support their hypothesis of local disease spread in a prion-like manner on the grounds that such data are not required from a methodological point of view.
A motor pool refers to all of the individual motor neurons that innervate a single muscle. Because of motor pools in the spinal cord are clustered in distinct columns of motor neurons extending over multiple spinal cord segments, a longitudinal study for estimating the number of motor units from individual muscles in ALS patients may provide a mechanistic insight into local disease spread.
Over the years a number of techniques have been developed to estimate the number of motor units in humans by defining a motor unit as the spinal motor neuron and its axon together with the muscle fibers it innervates. Motor unit number estimation (MUNE) is a technique that uses EMG to estimate the number of motor units in a muscle. Ridall PG et al.(3) developed a Bayesian statistical methodology to analyze electrophysiological data to provide an estimate of motor unit numbers. This method uses mathematical equations that express the basic elements of motor unit activation after electrical stimulation, allows for sources of variability and uncertainty, and has the capacity to estimate a larger number of motor units.
The exponential decimation of remaining lower motor neurons over time and different rates of progression have recently been demonstrated using the Bayesian MUNE (one of the most reliable methods for estimation of the total number of motor units) in both ALS patients and SOD1-linked familial ALS patients in all of the muscles examined (4). Furthermore, using SOD1 transgenic mice, MUNE values obtained with the Bayesian method showed a solid correlation with the histologically determined number of remaining lower motor neurons in the spinal cord. The exponential kinetics of neuronal cell loss are consistent with the 'one-hit' model of neurodegeneration described by Clarke et al. in which the death of a neuron is initiated randomly in time by a single, rare, catastrophic event independently of any neighboring neuron (5). Thus, the endogenous, stochastic occurrence of the one-hit events in a homogenous population of lower motor neurons may play a pivotal role in local disease spread. These features are clearly distinct from those of the prion-like propagation model of disease spread.
These findings, together with the study by Sekiguchi et al., suggest that lower motor neuron dysfunction defined by the electrophysiological evidence in ALS supports neither the 'simple propagation' nor the 'single seed' hypothesis.
1. Sekiguchi T et al. Spreading of amyotrophic lateral sclerosis lesions--multifocal hits and local propagation? J Neurol Neurosurg Psychiatry doi: 10.1136/jnnp-2013-305617
2. Polymenidou M, Cleveland DW. The seeds of neurodegeneration: prion-like spreading in ALS. Cell 2011; 147:498-508.
3. Ridall PG, Pettitt AN, Henderson RD, McCombe PA. Motor unit number estimation-a Bayesian approach. Biometrics. 2006; 62:1235-1250.
4. Baumann F et al. Quantitative studies of lower motor neuron degeneration in amyotrophic lateral sclerosis: evidence for exponential decay of motor unit numbers and greatest rate of loss at the site of onset. Clin Neurophysiol. 2012; 123:2092-8.
5. Clarke G, Lumsden CJ. Scale-free neurodegeneration: cellular heterogeneity and the stretched exponential kinetics of cell death. J Theor Biol. 2005; 233:515-525.
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