Good news!
"Now, in a study ... researchers report they have been able to prevent the buildup of alpha-synuclein in a mouse model of Parkinson’s, more than doubling how long the animals live. ...
amyotrophic lateral sclerosis (ALS), another neurodegenerative disease linked in some cases to aggregation of misfolded proteins. They uncovered that in a mouse model of ALS, a misfolded mutant version of the protein SOD1 (superoxide dismutase) aggregated inside different types of motor neurons, including those in the spinal cord, but it did not aggregate in those neurons responsible for moving the eyes. This paralleled observations that eye movement is spared in human ALS. ...
They found a number of candidates for producing resistance, and, over the course of three years, they tested 15 of these in ALS mice. They landed on a subunit of a potassium channel known as Kcnn1, which, when overexpressed in motor neurons of the ALS mouse model, prevented both protein aggregation in spinal cord motor neurons and early paralysis. ..."
From the significance and abstract:
"Significance
Parkinson’s Disease and several other neurodegenerative diseases are driven by misfolding and aggregation of the neuronal protein α-synuclein.
We studied a transgenic mouse model expressing the Parkinson’s-associated A53T mutant human α-synuclein, that succumbs with dystonic limbs at ~8 mo, with presence of disease-associated phospho-serine 129 α-synuclein in a variety of brain regions and in the spinal cord.
We identified a modifier of this clinicopathology, the neuronal overexpression of Kcnn1, a potassium channel subunit.
The modified mice survived to ~18 mo, exhibited a different clinical behavior—mild lower limb clasping—and did not form any significant level of the phosphorylated α-synuclein. Overexpression of Kcnn1 thus appears to be neuroprotective. Its action may have therapeutic implications.
Abstract
Synucleinopathies, including idiopathic Parkinson’s Disease, are driven by misfolding and aggregation of the 140 residue α-synuclein protein that plays a role in presynaptic vesicle regulation.
We describe effects of a modifier, neuronal overexpression of the mouse calcium-activated potassium channel subunit Kcnn1, on a mouse model in which transgenic Thy1.2-driven human A53T α-synuclein directs fully penetrant lethal motor disease.
Kcnn1 overexpression increased median survival of these mice from 8.5 to 18 mo, associated with an altered presentation from rapidly progressive dystonic-like behavior of the limbs to a later-onset (12 to 16 mo) and slowly progressive lower limb clasping when lifted by the tail.
At the tissue level, accretion of disease-associated phospho-serine 129 α-synuclein was prevented by overexpression of Thy1.2-driven Kcnn1 in many brain regions/spinal cord, where phospho-serine 129 α-synuclein copiously accreted in A53T mice at endstage. The action of blocking production of phospho-serine 129 α-synuclein was also observed in adult A53T mice injected presymptomatically with an AAV9 scCMV-Kcnn1 virus into the right superior colliculus.
At endstage ~2 mo later, the right superior colliculus exhibited overexpression of Kcnn1 and showed essentially no phospho-serine 129 α-synuclein, whereas the uninjected left superior colliculus exhibited copious phospho-serine 129 α-synuclein.
The neuroprotective action of Kcnn1 overexpression remains to be fully resolved, but the channel protein subunit, targeted to the ER membrane, has been shown to induce an ER stress response. This response, which may activate autophagy, along with potential channel formation, may diminish the rate of formation or lifetime of neurotoxic forms of A53T α-synuclein."
Fig. 2 Absence of phospho-serine129 α-synuclein (Psynuclein) immunostaining in 12 mo A53T/Kcnn1-6copy asymptomatic mouse as compared with A53T endstage (9 mo) mouse.
No comments:
Post a Comment