Biology subjects

Navarrete, W.

Publications and source records attributed to Navarrete, W..

5 recordsLinked to original sources

bioRxiv2026

Serum UCHL1, GFAP, and NfL track tyrosine hydroxylase loss in substantia nigra in two Rat Models of Parkinsons Disease

In Parkinsons disease (PD), blood-based (BB) biomarkers ubiquitin c-terminal hydrolase L 1 (UCHL-1), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) correlate with motor or cognitive impairment. However, it is unclear if blood levels of these biomarkers represent changes in nigrostriatal neuron viability or dopamine (DA) signaling. In 6-OHDA and Pink1 knockout (KO) rat models that showed progressive loss of DA tissue and tyrosine hydroxylase (TH) protein, we quantified UCHL-1, GFAP, and NfL expression in striatum and substantia nigra (SN) at 7- and 28-days in the 6-OHDA model and 7- and 18-month old in Pink 1 KO. Substantial changes in all biomarkers occurred with TH loss in SN, but not striatum, in both models. UCHL-1 levels increased against remaining TH protein. Accordingly, serum UCHL-1 levels increased 25% at 28 days post-6-OHDA and 18-month old Pink1 KO. GFAP and NfL levels increased in SN 28 days post-6-OHDA and 18 month-old Pink1 KO. Serum GFAP levels increased 28 days post-6-OHDA and 18 month-old Pink1 KO. Serum levels of NfL increased 28 days post-6-OHDA, and in 18 month-old Pink1 KO and wild-type, without influence by genotype. Expression levels of each biomarker were greater in the SN vs striatum, suggesting the SN contributes greater quantities of biomarkers to the blood and reflect TH loss therein. Taken together, our preclinical results show alignment between serum levels of UCHL-1, GFAP, and NfL and loss of TH and DA in the SN. As such, these biomarkers may be relevant peripheral indicators of deficient nigrostriatal DA signaling, and reflect nigrostriatal function in PD.

neuroscience↗

bioRxiv2025

Preservation of dopamine neurotransmission during nigrostriatal neuron loss in rat Parkinson model: evidence for increased dopamine signaling in substantia nigra

During progressive nigrostriatal neuron loss in Parkinsons disease (PD), compensatory mechanisms are thought to maintain dopamine (DA) signaling at levels sufficient to mitigate locomotor impairment prior to substantial neuron loss. Whereas increased DA turnover in striatum has been considered a keystone compensatory mechanism indicative of augmented DA signaling, recent work indicates that increased DA biosynthesis in substantia nigra (SN), not striatum, compensates for tyrosine hydroxylase (TH) protein and neuronal loss. To extend interrogation of compensatory mechanisms that augment DA signaling during nigrostriatal neuron loss, we contemporaneously evaluated extracellular DA against tissue DA levels and quantified TH protein in the striatum and SN. Our unilateral 6-hydroxydopamine (6-OHDA) lesion approach produces progressive neuronal loss between 7 and 28 days, enabling evaluation of multiple DA signaling components in striatum vs SN. Loss of TH was [~]90% in striatum and [~]70% in the SN by 7 days after lesion induction. However, whereas loss of tissue DA matched TH loss in striatum (>90%) on both days after lesion, tissue DA loss in SN occurred only at day 28 (36%), despite major TH loss by day 7. This preservation of nigral DA tissue levels during lesion progression was associated with increased extracellular DA in SN after K+-dependent depolarization in striatum, which was not evident in a sham-operation group at the same time, early after lesion induction, signifying a DA lesion-specific adaptation in SN. In contrast in the striatum, lesion abolished the robust increase in extracellular DA, as seen in the sham-operation group. Together, these results indicate compensatory mechanisms that augment nigrostriatal DA signaling are engaged in the SN, not striatum, during progressive nigrostriatal neuron loss.

neuroscience↗

bioRxiv2023

Moderate intensity aerobic exercise in 6-OHDA-lesioned rats alleviates established motor deficits and reduces neurofilament light and glial fibrillary acidic protein serum levels without increased striatal dopamine or tyrosine hydroxylase protein

BackgroundAlleviation of motor impairment by aerobic exercise (AE) in Parkinsons disease (PD) points to a CNS response that could be targeted by therapeutic approaches, but recovery of striatal dopamine (DA) or tyrosine hydroxylase (TH) has been inconsistent in rodent studies. ObjectiveTo increase translation of AE, 3 components were implemented into AE design to determine if recovery of established motor impairment, concomitant with >80% striatal DA and TH loss, was possible. We also evaluated if serum levels of neurofilament light (NfL) and glial fibrillary acidic protein (GFAP), blood-based biomarkers of disease severity in human PD, were affected. MethodsWe used a 6-OHDA hemiparkinson rat model featuring progressive nigrostriatal neuron loss over 28 days, with impaired forelimb use 7 days post-lesion, and hypokinesia onset 21 days post-lesion. After establishing forelimb use deficits, moderate intensity AE began 1-3 days later, 3x per week, for 40 min/session. Motor assessments were conducted weekly for 3 wks, followed by determination of striatal DA, TH protein and mRNA, and NfL and GFAP serum levels. ResultsSeven days after 6-OHDA lesion, recovery of depolarization-stimulated extracellular DA and DA tissue content was <10%, representing severity of DA loss in human PD, concomitant with 50% reduction in forelimb use. Despite severe DA loss, recovery of forelimb use deficits and alleviation of hypokinesia progression began after 2 weeks of AE and was maintained. Increased NfLand GFAP levels from lesion were reduced by AE. Despite these AE-driven changes, striatal DA tissue and TH protein levels were unaffected. ConclusionsThis proof-of-concept study shows AE, using exercise parameters within the capabilities most PD patients, promotes recovery of established motor deficits in a rodent PD model, concomitant with reduced levels of blood-based biomarkers associated with PD severity, without commensurate increase in striatal DA or TH protein.

neuroscience↗

bioRxiv2023

Differential expression of RET and GDNF family receptor, GFR-α1, between striatum and substantia nigra following nigrostriatal lesion: a case for diminished GDNF-signaling

Although glial cell line-derived neurotrophic factor (GDNF) showed efficacy in preclinical and early clinical studies to alleviate parkinsonian signs in Parkinsons disease (PD), later trials did not meet primary endpoints, giving pause to consider further investigation. While GDNF dose and delivery methods may have contributed to diminished efficacy, one crucial aspect of these clinical studies is that GDNF treatment across all studies began [~]8 years after PD diagnosis; a time point representing several years after near 100% depletion of nigrostriatal dopamine markers in striatum and at least 50% in substantia nigra (SN), and is later than the timing of GDNF treatment in preclinical studies. With nigrostriatal terminal loss exceeding 70% at PD diagnosis, we utilized hemi-parkinsonian rats to determine if expression of GDNF family receptor, GFR-1, and receptor tyrosine kinase, RET, differed between striatum and SN at 1 and 4 weeks following a 6-hydroxydopamine (6-OHDA) lesion. Whereas GDNF expression changed minimally, GFR-1 expression decreased progressively in striatum and in tyrosine hydroxylase positive (TH+) cells in SN, correlating with reduced TH cell number. However, in nigral astrocytes, GFR-1 expression increased. RET expression decreased maximally in striatum by 1 week, whereas in the SN, a transient bilateral increase occurred that returned to control levels by 4 weeks. Expression of brain-derived neurotrophic factor (BDNF) or its receptor, TrkB, were unchanged throughout lesion progression. Together, these results reveal that differential GFR-1 and RET expression between the striatum and SN, and cell-specific differences in GFR-1 expression in SN, occur during nigrostriatal neuron loss. Targeting loss of GDNF receptors appears critical to enhance GDNF therapeutic efficacy against nigrostriatal neuron loss. Significance StatementAlthough preclinical evidence supports that GDNF provides neuroprotection and improves locomotor function in preclinical studies, clinical data supporting its efficacy to alleviate motor impairment in Parkinsons disease patients remains uncertain. Using the established 6-OHDA hemi-parkinsonian rat model, we determined whether expression of its cognate receptors, GFR-1 and RET, were differentially affected between striatum and substantia nigra in a timeline study. In striatum, there was early and significant loss of RET, but a gradual, progressive loss of GFR-1. In contrast, RET transiently increased in lesioned substantia nigra, but GFR-1 progressively decreased only in nigrostriatal neurons and correlated with TH cell loss. Our results indicate that direct availability of GFR-1 may be a critical element that determines GDNF efficacy following striatal delivery. HighlightsGDNF expression was minimally affected by nigrostriatal lesion GDNF family receptor, GFR-1, progressively decreased in striatum and in TH neurons in SN. GFR-1 expression decreased along with TH neurons as lesion progressed GFR-1 increased bilaterally in GFAP+ cells suggesting an inherent response to offset TH neuron loss RET expression was severely reduced in striatum, whereas it increased in SN early after lesion induction

neuroscience↗

bioRxiv2022

Nigral-specific increase in ser31 tyrosine hydroxylase phosphorylation offsets dopamine loss and forestalls hypokinesia onset during progressive nigrostriatal neuron loss

Mechanisms that augment dopamine (DA) signaling to compensate for tyrosine hydroxylase (TH) loss and delay motor impairment in Parkinsons disease remain unidentified. The rat nigrostriatal pathway was unilaterally-lesioned by 6-OHDA to determine whether differences in DA content, TH protein, TH phosphorylation, or D1 receptor expression in striatum or substantia nigra (SN) aligned with onset of hypokinesia at two time points. At 7 days, DA and TH loss in striatum exceeded 95%, whereas DA was unaffected in SN, despite [~]60% TH loss. At 28 days, hypokinesia was established. At both time points, ser31 TH phosphorylation increased only in SN, corresponding to less DA versus TH loss. ser40 TH phosphorylation was unaffected in striatum or SN. By day 28, D1 receptor expression increased only in lesioned SN. These results indicate that increased ser31 TH phosphorylation and D1 receptor in the SN, not striatum, augment DA signaling against TH loss to mitigate hypokinesia. Highlights-Despite >90% TH and DA loss in striatum, open-field locomotor activity did not decrease -Early after lesion, DA and TH loss in striatum exceeded 90%. In contrast, DA loss did not occur despite 60% TH loss in substantia nigra (SN). -TH loss was progressive in the SN, with loss also spreading contralateral to lesion. -Loss of TH protein in SN preceded cell loss ipsilateral and contralateral to lesion, indicating first stages of nigrostriatal neuron loss begin with loss of TH protein loss. -TH phosphorylation at ser31 in SN was associated with less, if any, DA loss compared to TH protein loss. -TH phosphorylation at ser40 did not change in either region and at any time during TH loss, suggesting no contribution to differences in DA loss against TH loss. -Expression of the D1 receptor increased 2.5-fold in the SN late, but not early, after lesion, suggesting a post-synaptic receptor response to offset DA loss in SN. -No increases in TH phosphorylation or D1 receptor expression in striatum at any time after lesion induction, indicating that compensatory mechanisms occur only in substantia nigra, but not in striatum, to delay onset of hypokinesia.

neuroscience↗