Kinesin Expression in the Central Nervous System of Humans and Transgenic hSOD1G93A<b> </b>Mice with Amyotrophic Lateral Sclerosis

Abstract

Background: Amyotrophic lateral sclerosis is a fatal motor neuron degenerative disease. Most cases are sporadic (SALS), and approximately 10% are familial (FALS) among which over 20% are linked to the SOD1 mutation. Both SALS and FALS have been associated with retrograde axonal transport defects. Kinesins (KIFs) are motor proteins involved mainly in anterograde transport; however, some also participate in retrograde transport. Objective: The purpose of the study was to investigate and compare the expression of kinesins involved in anterograde (KIF5A, 5C) and retrograde (KIFC3/C2) axonal transport in SALS in humans and FALS in mice with the hSOD1G93A mutation. Methods: The studies were conducted on various parts of the CNS from autopsy specimens of SALS patients, and transgenic mice at presymptomatic and symptomatic stages using real-time quantitative PCR and reverse-transcription PCR. Results: All KIF expression in the motor cortex of individual SALS subjects was higher than in the adjacent sensory cortex, in contrast to the expression in control brains. It was also significantly higher in the frontal cortex of symptomatic but not presymptomatic mice compared to wild-type controls. However, the mean KIF expression in the SALS motor and sensory cortexes was lower than in control cortexes. To a lesser extent the decrease in KIF mean expression also occurred in human but not in mouse ALS spinal cords and in both human and mouse cerebella. Conclusion: Disturbances in kinesin expression in the CNS may dysregulate both anterograde and retrograde axonal transports leading to motor neuron degeneration.

Alteration of Motor Protein Expression Involved in Bidirectional Transport in Peripheral Blood Mononuclear Cells of Patients with Amyotrophic Lateral Sclerosis

“…KIFC3 is ubiquitously expressed, but its expression differs largely among tissues, e.g. it is high in epithelial cells of renal distal tubule but very low in the secretory epithelial cells of the small intestine, pancreas and various regions of the CNS [37,46]. Our present study indicates that it is also very low in PBMCs (approx.…”

“…Many papers indicated that disorders in the intracellular transport might be crucial for the initiation or progression of motor neuron degeneration [35,41,42,43,44]. In our previous studies, we observed important changes in the expression of tau isoforms, kinesins and dynactin in various regions of the CNS obtained from autopsies of SALS patients and transgenic mice with symptoms of motor neuron degeneration [36,37,38,45]. In the present work we investigated the expression of motor proteins in PBMCs obtained from a cohort of Polish SALS patients in comparison with healthy blood donors, and patients with other neurological diseases such as atypical parkinsonism and ALS-mimicking disorders.…”

“…Restricted access to human nervous tissue has promoted the use of transgenic animal disease models. Although very useful, they do not always reflect the clinical and pathological changes present in human subjects [37,38,40]. Many papers indicated that disorders in the intracellular transport might be crucial for the initiation or progression of motor neuron degeneration [35,41,42,43,44].…”

“…Kinesin and dynactin subunit expression on the mRNA level was studied by real-time quantitative PCR (qPCR), as indicated earlier [37,38]. Total RNA was extracted from PBMCs by a QIAamp RNA Blood Mini Kit (Qiagen, USA) according to the manufacturer's standard instructions.…”

“…In our earlier studies we showed several changes in the expression of crucial components of axonal transport in the CNS of humans with SALS and transgenic mice with SOD1-related ALS (familial ALS) [36,37,38]. In the present work we focused on the expression of motor proteins involved in the anterograde (KIF1B, KIF5C) and the retrograde (KIFC3, dynactin) transport in peripheral blood mononuclear cells (PBMCs) obtained from SALS patients, healthy control subjects and patients with other neurological diseases (disease control).…”