Thank You OpenMinds | Joud's Journey | A mother's testimony
January 28, 2021
ASKC/Neurogenetics Research:
Publications in 2020/early ‘21 totalled 15, exceeding all averages.
Grant applications submitted based on OM funded work number 9!
Research Highlights:
-Two novel Lebanese autism genes identified, UBLCP1 and UBR4.
-‘RitaT’, a new and rapid screening tool for autism was validated in Lebanon and is translated into Arabic.
-Negative impact of screen time on severity of autism in the Lebanese is published.
-Effectiveness of flupirtine to treat mice affected with CLN3 disease with sex differences defined is in print.
-Eye tracking and gender specificity in autism uncovered and published.
-Protective impact of breast feeding on autism in Lebanon has been shown.
-Hot of the presses… The CLN6 batten disease variant prevalent in Lebanon is being investigated in the Cln6nclfmouse model…
Fig 1a.
Fig 1b.
Visual Cliff test: 28-week old male Cln6nclf mice (n=3) could not discriminate between a safe zone and crossing over the cliff to the unsafe zone, spending equal time due to a significant loss in vision. Cln6nclf male mice spent more time over the cliff vs. age matched normal males (black bars) and less time in the safe zone (grey bars) (unpublished) .
The 2 autism genes identified affect vital protein degradation machinery in the cell, but differently.
It turns out that defective UBLCP1 gene can rescue and may be developped to treat defective UBR4.
Fig 2. Both UBLCP1/UBR4p impact proteolysis or protein breakdown
Central panel: Normal UBR4p is an E3 ligase. UBR4p substrates TRPV5p & ACLYp are linked to ASD. Normal UBLCP1p binds Rpn1p & dephosphorylates Rpt1p & inhibits proteasome assembly and activity.
Left panel: Mutated UBLCP1 does not lead to increased proteolytic cleavage.
Right panel: Mutant UBR4 impacts proteasome degradation via protein recognition/Ub-transfer from E2-ligase to proteins & targets them for degradation ↓Ub- proteins &↑TRPV5p &↑ACLYp.
Cells stained with antibodies to β3-tubulin of neuronal cells with UBR4 tag (red) and β3 tubulin (green). Cells over-expressing normal fragment exhibit a tubular pattern (upper panel) BUT a diffuse pattern lacking normal elongated cells in cells expressing mutant UBR4 domain fragment (lower panel). Yellow arrows point to cells with mutant UBR4 causing microtubule destabilization & cell disruption
Fig 4. Mutated UBLCP1p as a potential strategy to treat mutant UBR4
Left: UBR4 mutation leads to reduced protein degradation, and affects protein recognition/UB transfer from E2-ligase to targeted proteins, OR directly targets proteins for degradation. This causes accumulation of proteins. Right: Expressing mutant UBLCP1 rescues mutant UBR4 by ↑proteolysis (red arrow) &↑UBR4p activity (dashed orange) & ↑Ub-protein levels.
OpenMinds supports 5655 special needs services at the AUBMC SPECIAL KIDS CLINIC (ASKC)….
OpenMinds funds advances in local clinical/basic science of special needs at the NEUROGENETICS (NG) lab at AUBMC…
ASKC OpenMinds (OM) Clinical Packages:
Success Stories:
ASKC/Neurogenetics Research:
Research Highlights:
-Two novel Lebanese autism genes identified, UBLCP1 and UBR4.
-‘RitaT’, a new and rapid screening tool for autism was validated in Lebanon and is translated into Arabic.
-Negative impact of screen time on severity of autism in the Lebanese is published.
-Effectiveness of flupirtine to treat mice affected with CLN3 disease with sex differences defined is in print.
-Eye tracking and gender specificity in autism uncovered and published.
-Protective impact of breast feeding on autism in Lebanon has been shown.
-Hot of the presses… The CLN6 batten disease variant prevalent in Lebanon is being investigated in the Cln6nclf mouse model…
Fig 1a.
Fig 1b.
Visual Cliff test: 28-week old male Cln6nclf mice (n=3) could not discriminate between a safe zone and crossing over the cliff to the unsafe zone, spending equal time due to a significant loss in vision. Cln6nclf male mice spent more time over the cliff vs. age matched normal males (black bars) and less time in the safe zone (grey bars) (unpublished) .
The 2 autism genes identified affect vital protein degradation machinery in the cell, but differently.
It turns out that defective UBLCP1 gene can rescue and may be developped to treat defective UBR4.
Fig 2. Both UBLCP1/UBR4p impact proteolysis or protein breakdown
Central panel: Normal UBR4p is an E3 ligase. UBR4p substrates TRPV5p & ACLYp are linked to ASD. Normal UBLCP1p binds Rpn1p & dephosphorylates Rpt1p & inhibits proteasome assembly and activity.
Left panel: Mutated UBLCP1 does not lead to increased proteolytic cleavage.
Right panel: Mutant UBR4 impacts proteasome degradation via protein recognition/Ub-transfer from E2-ligase to proteins & targets them for degradation ↓Ub- proteins &↑TRPV5p &↑ACLYp.
Fig 3. Mutated UBR4p results in cell microtubule destabilization & cell disruption
Cells stained with antibodies to β3-tubulin of neuronal cells with UBR4 tag (red) and β3 tubulin (green). Cells over-expressing normal fragment exhibit a tubular pattern (upper panel) BUT a diffuse pattern lacking normal elongated cells in cells expressing mutant UBR4 domain fragment (lower panel). Yellow arrows point to cells with mutant UBR4 causing microtubule destabilization & cell disruption
Fig 4. Mutated UBLCP1p as a potential strategy to treat mutant UBR4
Left: UBR4 mutation leads to reduced protein degradation, and affects protein recognition/UB transfer from E2-ligase to targeted proteins, OR directly targets proteins for degradation. This causes accumulation of proteins. Right: Expressing mutant UBLCP1 rescues mutant UBR4 by ↑proteolysis (red arrow) &↑UBR4p activity (dashed orange) & ↑Ub-protein levels.