TY  - JOUR
AB  - BACKGROUND: Although an increasing role of genetic susceptibility has been recognized, the role of environmental risk factors in amyotrophic lateral sclerosis (ALS) etiology is largely uncertain; among neurotoxic chemicals, epidemiological and biological plausibility has been provided for pesticides, the heavy metal lead, the metalloid selenium, and other persistent organic pollutants. Selenium involvement in ALS has been suggested on the basis of epidemiological studies, in vitro investigations, and veterinary studies in which selenium induced a selective toxicity against motor neurons. OBJECTIVE: Hypothesizing a multistep pathogenic mechanism (genetic susceptibility and environmental exposure), we aimed to study selenium species in ALS patients carrying disease-associated gene mutations as compared to a series of hospital controls. METHODS: Using advanced analytical techniques, we determined selenium species in cerebrospinal fluid sampled at diagnosis in 9 ALS patients carrying different gene mutations (C9ORF72, SOD1, FUS, TARDBP, ATXN2, and TUBA4A) compared to 42 controls. RESULTS: In a patient with the tubulin-related TUBA4A mutation, we found highly elevated levels (in μg/L) of glutathione-peroxidase-bound selenium (32.8 vs. 1.0) as well as increased levels of selenoprotein-P-bound selenium (2.4 vs. 0.8), selenite (1.8 vs. 0.1), and selenate (0.9 vs. 0.1). In the remaining ALS patients, we detected elevated selenomethionine-bound selenium levels (0.38 vs. 0.06). CONCLUSIONS: Selenium compounds can impair tubulin synthesis and the cytoskeleton structure, as do tubulin-related gene mutations. The elevated selenium species levels in the TUBA4A patient may have a genetic etiology and/or represent a pathogenic pathway through which this mutation favors disease onset, though unmeasured confounding cannot be excluded. The elevated selenomethionine levels in the other patients are also of interest due to the toxicity of this nonphysiological selenium species. Our study is the first to assess selenium exposure in genetic ALS, suggesting an interaction between this environmental factor and genetics in triggering disease onset.
AU  - Mandrioli, J.*
AU  - Michalke, B.
AU  - Solovyev, N.
AU  - Grill, P.
AU  - Violi, F.*
AU  - Lunetta, C.*
AU  - Conte, A.*
AU  - Sansone, V.A.*
AU  - Sabatelli, M.*
AU  - Vinceti, M.*
C1  - 51263
C2  - 42811
SP  - 171-180
TI  - Elevated levels of selenium species in cerebrospinal fluid of amyotrophic lateral sclerosis patients with disease-associated gene mutations.
JO  - Neurodegener. Dis.
VL  - 17
IS  - 4-5
PY  - 2017
SN  - 1660-2854
ER  - 

TY  - JOUR
AB  - Our knowledge about the normal generation of midbrain dopaminergic neurons in vivois still rudimentary, despite many attempts to recapitulate the underlying events in vitro. Because the loss of these neurons is implicated in Parkinson's disease, this lack of information is one of the major drawbacks in the development of better therapies for this severe human neurological disorder. Recently, substantial advances have been made by demonstrating that the secreted molecule Wnt1 regulates a genetic network, including the transcription factors Otx2 and Nkx2-2, for the initial establishment of the dopaminergic progenitor domain in the mammalian ventral midbrain. In addition, Wnt1 appears to regulate the differentiation of the postmitotic progeny of these precursors by initiating the expression of midbrain dopaminergic-specific transcription factors. A genetic cascade controlled by the secreted molecule Sonic hedgehog, including the transcription factors Lmx1a, Msx1 and Nkx6-1, acts in parallel with the Wnt1-regulated network to establish the midbrain dopaminergic progenitor domain. The Sonic-hedgehog-controlled cascade may diverge from the Wnt1-regulated network at later stages of neural development through induction of proneural transcription factors required for the acquisition of generic neuronal properties by the midbrain dopaminergic progeny. Here we provide a brief overview of these regulatory gene networks.
AU  - Prakash, N.
AU  - Wurst, W.
C1  - 4171
C2  - 24860
SP  - 333-338
TI  - A Wnt signal regulates stem cell fate and differentiation in vivo.
JO  - Neurodegener. Dis.
VL  - 4
IS  - 4
PB  - Karger
PY  - 2007
SN  - 1660-2854
ER  -